Note: Descriptions are shown in the official language in which they were submitted.
-1- 16068Y
1 TITLE OF THE INVENTION
Chemical Compounds and Processes
DESCRIPTION OF THE INVENTION
. . . _
This invention relates to novel interphenylene
9-thia-11-oxo-12-azaprostanoic acids, salts, and deriva-
tives which are represented by the following formula:
(I)m
R~s~(cH2)n-A-R
\ Z/C \ 4
R -O
wherein R is selected from the group consisting of carboxy
and a carboxy salt which incorporates a pharmaceutically
acceptable cation, such as metal cations derived from
alkali metals, alkalihe earth metals, and amines such as
ammonia, primary and secondary amines and quaternary
ammonium hydroxides. Especially preferred metal cations
are those derived from alkali metals, e.g., sodium, potas-
sium, lithium, and the like, and alkaline earth metals,
e.g., calcium, magnesium, and the like, and other metals,
i.e., aluminum, iron, and zinc.
Pharmaceutically acceptable cations derived from
primary, secondary, or tertiary amines, or quaternary
,-
~
-2- 16063Y
1 ammonium hydroxides are methylamine, dimethylamine, 1~
methylpiperazine, trimethylamine, ethylamine, N-methyl-
hexylamine, benzylamine, a-phenethylamine, ethylene-
diamine, piperidine, morpholine, pyrrolidine, 1,4-
dimethylpiperaæine, ethanolamine, diethanolamine, trieth-
anolamine, tris(hydroxymethyl)aminomethane, N-methyl-
glucamine, N-methylglucosamine, ephedrine, procaine,
tetramethylammonium hydroxide, tetraethylammonium hydrox-
ide, benzyltrimethylammonium hydroxide, and the like.
R is also selected from alkoxycarbonyl, e.g., a
carboxy ester of the formula -CooR5 wherein R5 is alkyl
having l-lO carbon atoms.
R is further selected from the group
o
-C-NH-R6 wherein R is amino (NH2) or methylsulfonyl
(CH3SO2).
A is a divalent monocyclic substituted or un-
substituted aromatic or a 5-membered sulfur or oxygen
containing heterocyclic ring preferably a p-phenylene or
a m-phenylene or substituted phenylene derivatives in
which one or two of the phenylene hydrogens is replaced by
a methyl or a halo, preferably chloro, substitutent or 2,5-
thienylene or 2,5-furylene. Examples of such substituents
are p-phenylene ( ~ ) or m-phenylene ( ~ ) where
Xr Xr
X is either hydrogen or chloro or methyl, and r is 0, l,
or 2, or 2,5-thienylene ( ~ ) or 2,5-furylene ( ~ ).
n is 3 or 4.
m is 0, l, or 2.
Rl is hydrogen, an isotope thereof especially
deuterium, or methyl.
l~v2a~Z~
-3- 16068Y
1 Z is alkylene or unsaturated alkylene of from
2-3 carbon atoms preferably ethylene (-CH2CH2-), trimeth-
ylene (-CH2CH2CH2-), cls-propenylene
H ~C C ~ ), trans-propenylene ( 2~ C=C ~H
propynylene (-CH2C-C-).
R is hydrogen or lower alkanoyl especially
acetyl.
R3 is hydrogen or a straight chain lower alkyl
of one to three carbon atoms.
R4 is lower straight chain or branched alkyl
having from 3 to 7 carbon atoms (especially propyl, butyl,
amyl, isoamyl, heptyl, and l,l-dimethylpentyl), unsatura-
ted lower alkyl including 4-pentenyl, substituted lower
alkyl such as polyfluoroal~syl, as for example 5,5,5-tri-
fluoropentyl, and lower alkoxy methylene such as -CH2-o-R7
preferably where R is selected from the group consisting
of lower alkyl, straight or branched, with from 2 to 5
carbon atoms; or R3 and R4 taken together with the carbon
atom connecting R3 and R is a cyclic substituent com-
- 20 prising an alicyclic ring, bridged or unbridged, of from
5 to 9 carbon atoms such as cyclopentyl, cyclohexyl,
cyclooctyl, or bicyclo [3.3.1] nonyl, or a heterocyclic
: ring containing sulfur or oxygen and with from 5 to 7
ring-forming carbon atoms such as tetrahydropyranyl or
tetrahydrothiopyranyl.
A preferred sub-group of the compounds of this
invention are compounds of the formula:
Rl S ~ ( 2)n ~ COOH
O / R
HO
z~s
-4- 16068Y
1 wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3
or 4; R1 is hydrogen, deuterium, or methyl; Z is ethylene,
trimethylene, cis or trans-propenylene, or propynylene;
R3 is hydrogen or lower alkyl of 1-3 carbon atoms; and R4
is 4-pentenyl, 5,5,5-trifluoropentyl, or lower straight
or branched chain alkyl of 3-7 carbon atoms. Examples of
compounds included within this group are:
4-~3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]-
propyl~ benzoic acid;
4-~3-[3-(3-hydroxydecyl)-4-oxo-2-thiazolidinyl]-
propyl}benzoic acid;
4-~3-[3-(3-hydroxy-4,4-dimethyloctyl)-4-oxo-2-
thlaæolidinyl]propyl}benzoic acid;
4-~3-[3-(3-hydroxy-7-octenyl)-4-oxo-2-thiazolid-
inyl]propyl~benzoic acid;
4-~3-[3-(3-hydroxy-8,8,8-trifluorooctyl)-4 -oxo-2-
thiazolidinyl]propyl~benzoic acid; and
4-~3 ~3-(3-hydroxy-3-methyloctyl)-4-oxo-2-thia-
zolidinyl]propyl~benzoic acid.
Another preferred sub-group of the compounds of
this inVention are selected from the group consisting of
a compound of the formula:
Rl Sl (CH2) n~COOH
R ~ ~ Z-CH-R4
OH
wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3
or 4; Rl is hydrogen, deuterium, or methyl; Z is ethylene,
trimethylene, ciS or trans-propenylene, or propynylene;
and R4 is CH20R7 wherein R7 is lower straight or branched
chain alkyl of 2-5 carbon atoms. An example of such a
compound is 4-~3-[3-(3-hydroxy-4-propoxybutyl)-4-oxo-2-
thiazolidinyl]propyl~benzoic acid.
2~5
~5~ 16068Y
1 Another preferred sub-group of the compounds of
this invention is selected from the ~roup consisting of a
compound of the formula:
(I)m
Rl S ~( CH2 ) n~COOH
R ~ ~ z-C/ ~
wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3
or 4; m is 0, 1, or 2; Rl is hydrogen, deuterium, or
methyl; z is ethylene, trimethylene, propenylene, or
propynylene; y is 0, 2, or 3; and W is polymethylene of
2-6 carbon atoms. Examples of such compounds are:
4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~benzoic acid
~ 4-~3-[3-[2-(1-hydroxycyclopentyl)ethyl]-4-oxo-2-
: thiazolidinyl]propyl~benzoic acid
4-~3-[3-[2-(1-hydroxycycloheptyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl}benzoic acid
4-~3-[3-[2-(1-hydroxy-4,4-dimethylcyclohexyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl}benzoic acid
4-~3-[3-[2-(9-hydroxy-9-bicyclo[3.3.1]nonyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl¦benzoic acid
4-~4-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]butyl}benzoic acid
4-~3-[3-[3-(1-hydroxycyclohexyl)propyl]-4-oxo-2-
thiazolidinyl]propyl~benzoic acid
4-~3-[3-[3-(1-hydroxycyclohexyl)-(2)-2-propenyl]-
4-oxo-2-thiazolidinyl]propyl}benzoic acid
4-~3-[3-[3-(1-hydroxycyclohexyl)-(E)-2-propenyl]-
4-oxo-2-thiazolidinyl]propyl3benzoic acid
4-~3-[3-[3-(1-hydroxycyclohexyl)-2-propynyl]-4-
oxo-2-thiazolidinyl]propyl}benzoic acid
4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~-3-chlorobenzoic acid
42~5
-6- 16068Y
1 4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~-2-chlorobenzoic acid
4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl}-3-methylbenzoic acid
4-~3-[3-[2-(l-hydroxycyclohexyl)ethyl]-ll4-di
2-thiazolidinyl]propyl~benzoic acid
4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-1,1,4 tri-
oxo-2-thiazolidinyl]propyl}benzoic acid
4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-5,5-dimethyl-
4-oxo-2-thiazolidinyl]propyl~benzoic acid
4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-5,5-di-
deuterio-4-oxo-2-thiazolidinyl]propyl~benzoic acid
A still further preferred sub-group of this
invention is selected from the group consisting of a com-
pound of the formula~
(I)m ~ COOH
Rl S ~ (CH2)n ~
>< N Xr
O
HO
wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3
or 4; m is 0, 1, or 2; Rl is hydrogen or methyl; Z is
ethylene, trimethylene, propenylene, or propynylene; and
y is 4 to 8. ~ example of a compound of this sub-group
is 3-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thia-
zolidinyl]propyl~benzoic acid.
Still further sub-groups of preferred compounds
of this invention are represented by the formulas:
Rl S ~( CH2 ) n~COOH
Rl>S-- ~ Z_C~CH2 ) y
HO
x~
-7- 16068Y
1 wherein n is 3 or 4; Rl is hydrogen or methyl~ Z is
ethylene, trimethylene, propenylene, or propynylene; and
y is 4 to 8; an example of which is 5-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~thiophene-
2-carboxylic acid;
Rl S~ ( CH2 ) n~COOH
R ~ ~ Z-C ~ CH2)y
HO
wherein n is 3 or 4; Rl is hydrogen or methyl; Z is
ethylene, trimethylene, propenylene, or propynylene; and
- y is 4 to 8; an example of which is 5~-3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~furan-2-
carboxylic acid; and
Rl s~ CH2~ n~COOH
Z-C ~ w A
O / \(CH2)y~
HO
wherein n is 3 or 4; Rl is hydrogen or methyl; Z is
ethylene, trimethylene, propenylene, or propynylene; w
and y are each 1 to S with the sum of w and y being from
4 to 6; and A is oxygen or sulfur.
Other derivatives within the scope of the pres-
ent invention include 4-~3-[3-[2-(1-hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl7benzoate, 4-~3-[3-[2-
(l-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-
benzoic acid hydrazide, N-methylsulfonyl-4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-
~g.~ ;5
-8- 16068Y
1 benzamide, and 4-~3-[3-[2-(1-acetoxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoi~ acid.
The carbon atom in the thiazolidinone ring
marked by an asterisk (*) is asymmetric in all compounds
of this invention. In compounds wherein R3 and R4 are
dissimilar, the carbon atom bearing these groups is
asymmetric. Thus, the compounds of this invention are
obtained as racemates when only the former carbon is
asymmetric and they are obtained as mixtures of diastere-
omers when both carbon atoms are asymmetric. This inven-
tion includes the separate stereoisomers which are com-
ponents of these mixtures of isomers. The separate stereo-
isomers have biological activity similar to those of the
racemates and diastereomeric mixtures, which biological
activity varies from compound to compound.
BACKGROUND OF THE INVENTION
The compounds of formula I are described as
interphenylene 9-thia-11-oxo-12-azaprostanoic acids and
derivatives as a means of describing the structural rela-
tionship to prostanoic acid, which has the carbon skeletonof the natural prostaglandins as shown in the following
formula:
C02H
/g~r"~~
~ ~
prostanoic acid
The prostaglandins constitute a class of highly
functionalized C20 fatty acids. They have been shown to
occur extensively in low concentrations in mammalian tis-
sues where they are both rapidly anabolized and catabol-
ized and to exhibit a broad spectrum of pharmacological
~.2'~ ti
-9- 16068Y
1 activities including prominent roles in (a) functional
hyperemia, (b) the inflammatory response, (c) the central
nervous system, (d) transport of water and electrolytes,
and (e) regulation of cyclic AMP. Further details con-
cerning the prostaglandins can be found in recent reviewsof their chemistry [3. E. Pike, FORTSCHR. CHEM. ORG.
NATURST., 28, 313 (1970) and G. F. Bundy, A. REP. IN MED.
CHEM., 7, 157 (1972); biochemistry [J. W. Hinman, A. REV.
BIOCHEM., 41, 161 (1972)]; pharmacology [J. R. Weeks, A.
REV. PHARM., 12, 317 (1972)]; physiological significance
[E. W. Horton, PHYSIOL. REV. 49, 122 (1969)]; and general
clinical application [J. E. Hinman, POSTGRAD MED. J. 46,
562 (1970)].
In accordance with the present invention, there
is provided a novel group of aza-prostanoic acids of
formula I hereinabove. Surprisingly, the compounds of
the present invention have a specific range of biological
activities and do not possess the broad spectrum of bio-
logical activity possessed by the natural prostaglandins
and their analogs. The compounds of the present inven-
tion, for example, are completely inactive in the mouse
ovary prostaglandin assay which measures increases in
cellular cyclic adenosine monophosphate levels ordinarily
caused by prostaglandins and related compounds.
The compounds of the present invention, in
addition, are highly potent, orally effective renal vaso-
dilators having a sustained biological action but with
reduced side effects and, therefore, are useful for the
treatment of patients with renal impairment. Included
in this group are patients with hypertension, renal fail-
ure, congestive heart failure, glomerulonephritis, uremia,
and chronic renal insufficiency. The compounds of this
invention by virtue of their renal vasodilatory activity
.
-10- 16068Y
l improve renal function both when used alone or in conjunc-
tion with other renal agents. An example of a compound
with high renal vasodilatory activity is 4-~3-[3-[2-(l-
hydroxycyclohexyl~ethyl]-4-oxo-2-thiazolidinyl]propyl~-
benzoic acid.
The compounds of the present invention are also
orally effective antihypertensive agents and as such are
useful in reducing blood pressure in individuals affected
by this problem. The compounds of the present invention
are surprisingly potent in their antihypertensive effect
when compared with structurally related compounds.
The compounds of this invention have adjunctive
properties which give them added utility for the treatment
of renal disease. Such properties include antiasthmatic
lS (bronchorelaxant), cardiotonic, and immunoregulant acti-
vities.
A further area of usefulness of the compounds
of this invention is in the prevention of organ trans-
plant rejection.
Processes for the Synthesis of the Compounds of this
Invention
One of the preferred groups of compounds of the
present invention are the carboxylic acids represented by
formula II:
Rl s~(CE~2) n-A-co2H
O / R II
HO
wherein A, N, Rl, Z, R3, and R4 are as previously defined.
These acids can be synthesized by any of three processes
which will now be defined.
~l~.Z~Z~:S
~ 16068Y
1 Process 1
Step 1: OHC-(CH2)n-A-CO2R8 III
(R8 is straight chain lower alkyl)
0-5C. R3
Na2S4 H2N-Z-C / 4 IV
0,5-4 hours THPO
(R3, R4, and Z as defined
previously;
THP=tetrahydropyranyl)
10 solid HC /( 2)n 2
removed.ll R3 V
V in ~ Z-C ~ 4
THPO
benzene-toluene ¦ ~ C / VI
reflux to remove Rl /l
water CO2H
\ /
Rl S ~ ( CH2 ) n-A-co2R8
O / R VII
THPO
HCl in methanol or
ethanol, room tempera-
ture 1-24 hours.
Z~.5
-12- 16068Y
Rl Sl~ (CH2) n-A-co2R8
O / R VIII
HO
1 dil. NaOH, LioH, or
KOE~ in methanol
II
Process 2: III
benzene-toluene ~ C ~ XI
acid trace, reflux Rl~ ¦
to azeotrope water CONH2
\ /
Rl Sl~ ( CH2 ) n-A-C02R8
Rl ~ NH XII
NaH in DMF or DMF- , R3
benzene or DMF- X-Z-C XIII
toluene, 35-37C. / \ R4
(R3 and R4 as previously
\ defined)
,
1:1 .2~ LS
-13- 16068Y
R S ~ (CH2)n-A-co2R8
O / R XIV
PO
1 acid hydrolysis
of THP
\ /
The thiazolidinone esters XIV (P = acetyl) or VIII are
subjected to basic hydrolysis as shown in the last step
of Process 1. The thiazolidinone carboxylic acid of
formula II is thereby produced.
Process 3: Preparation of II with Tertiary OH
R3 is lower alkyl, R4 is an alicyclic or hetero-
cyclic ring, and Z is ethylene or trimethylene.
Anion of XII
X- Z - C~ g XV
35-75C.
3-10 hours` (X =Br, I;
Zl=CH2-CH2, -CH2CH2CH2-;
R3 & R9 together are ali-
cyclic or heterocyclic
ring; or
R3=lower alkyl and
R9=alkyl, 3-butenyl, or
C3HgCF3)
\ /
' ~ ' `
: .
x~
-14- 16068Y
R S l (CH2)n-A-co2R8
Rlk~ N\Z1 C~R XVI
CF3COOH
10-25C. for
2- 6 hours ~
Rl S ~ ( CH2 ) n~A- CO~R8
R~-- ~ Zl_C~ g XVII
CF3COO
twherein all groups are as defined previously)
basic
hydrolysis
R~S~(CH2) n-A-C02H
\ Z -C\ g IIa
HO
(wherein all groups are as defined previously)
Alternatively, the order of the last two reaction steps
can be reversed.
These products may be derivatized in a variety
of ways to yield other products of formula II by methods
known to one skilled in the art.
.
2~i
-15- 16068Y
1 EXAMPLE 1
Preparation of 4-~3-[3-(3-Hydroxyoctyl)-4-oxo-2-thiazoli-
dinyl]propyl~benzoic Acid
Step A: Preparation of Ethyl 4-(4-Oxobutyl)benzoate
Step A-l: Preparation of Ethyl 4-~3-[2-(1,3-Dioxolanyl)]-
propyl}benzoate
n-Butyl lithium solution (2.29M in hexane, 35
ml., 80 mmol.) is added to a stirred solution of di-i-
propylamine (8.0~ g., 80 mmol.) in anhydrous THF (tetra-
hydrofuran, 120 ml.) and HMPA (hexamethylphosphonamide,10 ml.) under nitrogen atmosphere. Subsequent addition
of a THF (20 ml.) solution of p-toluic acid (5.44 g., 40
mmol.) results in a deep greenish-brown solution. The
deep-colored solution is stirred at 0C. for 30 minutes
before being treated with a THF (10 ml.) solution of
2-(2-bromoethyl)-1,3-dioxolane. The resulting mixture is
stirred for 30 minutes, and then quenched with cold water.
The organic phase is separated, the aqueous layer is
acidified with hydrochloric acid (2N), and then extracted
with ether. The latter ethereal extraction is washed
with water, dried over anhydrous magnesium sulfate, fil-
tered, and concentrated to give a solid residue.
The solid residue is dissolved in DMF (dimethyl-
formamide, 50 ml.) and then successively treated with
potassium carbonate (69.1 g., 50 mmol.) and ethyl iodide
(9.36 g., 60 mmol.). The resulting mixture is stirred at
ambient temperature for 16 hours. Additional ethyl iodide
(1 g.) is added to the reaction mixture, following by
heating on a steam bath for 10 minutes. The reaction mix-
ture is then allowed to cool to room temperature, quenchedwith cold water, and extracted with ether. The ethereal
extract is washed successively with diluted hydrochloric
acid and 5% sodium bicarbonate, dried over anhydrous mag-
nesium sulfate, filtered, and evaporated to leave an oil
~L~.Z~2~5
-16- 16068Y
1 residue. The residue is then fractionated to give ethyl
benzoate ~2 g., b.p. 55-59C. at 0.05 mmHg.), and the
desired title compound (5.81 g., 22 mmol., 55~, b.p. 135-
140C. at 0.05 mm.), pmr (CDC13) J 1. 39 (3H, t, J=7Hz),
1.76 (2H, m), 2.74 (2H, m), 3.90 (4H, m), 4.40 (2H, q,
J=7Hz), 4.89 (lH, t), 7.26 (2H, d, J=8Hz), 8.0 (2H, d,
J=8HZ) .
Step A-2: Preparation of Ethyl 4-(4-Oxobutyl)benzoate
A mixture of ethyl 4-~3-[3-(1,3-dioxolanyl)]-
propyl~benzoate (0.90 g., 3.4 mmol.), water (7 ml.),
acetic acid (14 ml.) plus five drops of concentrated
hydrochloric acid is stirred at 50-65C. for 4 hours.
The reaction mixture is diluted with water and extracted
with ether. The ethereal extract is then washed with
water twice, 5% sodium bicarbonate solution three times
till neutral, dried over anhydrous magnesium sulfate, and
evaporated to gi~e the desired title compound as a pale
yellow oil, pmr (CDC13) ~ 1.40 (3H, t, J=7Hz), 1.7 ~ 3.0
(6H, m), 4.40 (2H, q, J=7Hz), 7.25 (2H, d, J=8Hz), 8.0
(2H, d, J=8Hz), 9.80 (lH, m).
Step B: Preparation of l-Amino-3-(tetrahydro-2H-pyran-2-
yloxy)octane
Step B-l: Preparation of 3-Hydroxycaprylonitrile
A l.9M solution (21 ml. 40 millimole) of n-butyl
lithium in hexane is added cautiously to a stirred solu-
tion of freshly distilled diisopropylamine (4.04 g., 40
millimole) in anhydrous tetrahydrofuran (60 ml.) main-
tained at 0C. under a nitrogen atmosphere. The resultingsolution is stirred at ambient temperature for 15 minutes,
cooled to -78C., and treated with a solution of anhydrous
acetonitrile (1.64 g., 40 millimole) in anhydrous tetra-
hydrofuran (5 ml.). The resulting turbid suspension is
4Z~5
-17- 16068Y
1 stirred and maintained at -78C. for 30 minutes and then
treated with a solution of hexanal t4.0 g., 40 millimole)
in anhydrous tetrahydrofuran (5 ml.). After attaining a
clear, yellow reaction solution, cooling at -78C. is
maintained for an additional 15 minutes. The cold reac-
tion solution is treated with 2N hydrochloric acid ~50
ml.) and extracted with ether (100 ml.). The organic
extract is washed with water (50 ml.) and 5% aqueous
sodium bicarbonate (50 ml.), dried over magnesium sulfate,
filtered and evaporated ln vacuo, leaving the title com-
pound as a pale yellow oil (5.2 g., 92%), pmr (CDC13) ~
0.97 (3H, t), 2.55 (2H, d), 3.10 (H, s) and 3.93 (H, bs).
Step B-2: Preparation of 3-(Tetrahydro-2H-pyran-2-yloxy)-
caprylonitrile
A mixture of 3-hydroxycaprylonitrile (5.2 g.,
36.8 millimole), dihydropyran (3.8 g., 45 millimole), and
p-toluenesulfonic acid-hydrate (catalytic amount) is
stirred at 25C. for 16 hours, then diluted with ether
- (100 ml.). The resulting solution is washed with 5% aque-
ous sodium hydroxide (25 ml.) and water (2 x 25 ml.),
dried over magnesium sulfate, and filtered. Evaporation
of the filtrate in vacuo affords the title compound as a
pale yellow oil (7.9 g., 95%), pmr (CDC13) dr 0.93 (3H, t),
2.54 (2H, q) and 4.68 (H, m).
Step B-3: Preparation of l-Amino-3-(tetrahydro-2H-pyran-
2-yloxy)octane
A solution of 3-(tetrahydro-2H-pyran-2-yloxy)-
caprylonitrile (4.05 g., 18 millimole) in dry ether (10
ml.) is added dropwise to a stirred suspension of lithium
aluminum hydride (0.76 g., 20 millimole) in dry ether (90
ml.) maintained under a nitrogen atmosphere. Upon com-
pletion of the addition, the reaction mixture is stirred
and heated at reflux for 16 hours. After cooling to 25C.,
-18- 16068Y
1 the reaction mixture is treated successively with water
(1 ml.), and 5% aqueous sodium hydroxide (3 ml.) added
dropwise with caution, affording a fine suspension which
is cooled to and maintained at 0-5C. for 30 minutes, and
filtered. In vacuo evaporation of the solvent leaves the
title compound as a pale yellow oil (3.95 g., 95%), pmr
~CDC13) S 0.88 (3H, t), 2.79 (2H, m) and 4.68 (H, bs).
Step C: Preparation of Ethyl 4-~3-[3-(3-Hydroxyoctyl)-4-
oxo-2-thiazolidinyl]propyl~benzoate
Ethyl 4-(4-oxobutyl)benzoate (4.63 g., 21 mmol.)
is added dropwise to l-amino-3-(tetrahydro-2H-pyran-2-yl-
oxy)octane (4.82 g., 21 mmol.) at ambient temperature.
The resulting mixture is stirred for 15 minutes before
adding anhydrous sodium sulfate (4 g.), and then stirred
for 1 hour. The solid is subsequently removed by filtra-
tion and washed with a small quantity of benzene. The
combined filtrate and washings are diluted with benzene
(70 ml.) and then treated with mercaptoacetic acid (1.93
g., 21 mmol.). The resulting solution is refluxed in a
Dean-Stark apparatus for 3 hours. The reaction mixture is
allowed to cool to room temperature, washed successively
with dilute hydrochloric acid, 5% sodium bicarbonate,
dried over anhydrous magnesium sulfate, and concentrated
to give an oil residue. A methanol solution (50 ml.) of
the oil residue is treated with concentrated hydrochloric
acid (0.2 ml.) and then stirred at ambient temperature for
16 hours. The reaction mixture is diluted with cold water,
followed by extraction with ether. The ethereal extract
is washed with water, 5% sodium bicarbonate, dried over
anhydrous magnesium sulfate t and filtered. Evaporation
of the filtrate in vacuo provides an oil residue which is
then applied to a silica gel column (300 g.) with chloro-
form. Elution with chloroform-methanol (100:1; v:v;
s
19- 16068Y
1 1950 ml.) provides impure material; further elution with
the sa~e eluant (450 ml.) gives the title compound as a
pale yellow oil (2.80 g., 6.64 mmol., 31%), pmr (CDC13)
~ 0.90 (3H, t), 1.40 (3H, t), 3.53 (2H, s), 4.40 (2H, q),
4.70 (lH, m), 7.22 (2H, d), 8.0 (2H, d).
Step D: Preparation of 4-~3-[3-(3-Hydroxyoctyl)-4-oxo-2-
thiazolidinyl)propyl~benzoic Acid
Sodium hydroxide solution (SN, 2.5 ml., 12.5
mmol.) is added dropwise to a stirred mixture of ethyl
4-~3-[3-(hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl}benz-
oate (2.80 g., 6.64 mmol.) in aqueous methanol (25 ml.
methanol plus 5 ml. water) maintained at 0C. The resul-
ting mixture is allowed to warm to room temperature and
stirred for 3 hours. Then, the reaction mixture is
diluted with water, and extracted with ether. The aqueous
phase is separated, acidified with 2N hydrochloric acid
(10 ml.), and extracted with ether. This ethereal extract
is washed with water, dried over anhydrous magnesium sul-
fate, concentrated in vacuo to yield an oil residue. The
oil residue is then applied to a silica gel column (75 g.)
with chloroform. Elution with chloroform-acetic acid
(25:1; v:v; 410 ml.) gives impure material. Continued
elution with the same eluant (420 ml.) provides the de-
sired title compound as a viscous pale yellow oil, ir
(NaCl) 1700, 1665 cm 1, pmr (CDC13) ~ 0.92 (3H, t), 3.60
(2H, s), 4.72 (lH, m~, 7.30 (2H, d), 8.08 (2H, d).
~ ~r~
-20- 16068Y
1 EXAMPLE 2
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl}benzoic Acid
Step A-l: Preparation of 2~ Hydroxycyclohexyl)aceto-
nitrile
n-Butyl lithium (1.6M solution in n-hexane,
125 ml., 0.2 mol.) is added to a solution of di-i-propyl-
amine ~20.2 g., 0.2 mol.) in THF (280 ml.) at 0C. under
nitrogen atmosphere. The resulting mixture is then cooled
to -78C. (dry ice - isopropanol), followed by the addi-
tion of a THF (10 ml.) solution of acetonitrile (8.20 g.,
0.2 mol.). The resulting mixture is stirred at -78C. for
20 minutes, then treated with cyclohexanone (19.6 g., 0.2
mol.) and HMPA (15 ml.). Stirring is continued at -78C.
for 45 minutes before the reaction mixture is allowed to
warm to room temperature. The reaction mixture is diluted
with ether (100 ml.), ~uenched with water (200 ml.), and
acidified with 3.5N hydrochloric acid (140 ml.). The
organic phase is separated, washed with water (200 ml.)
and S% sodium bicarbonate (100 ml.), dried over anhydrous
magnesium sulfate, and filtered. Evaporation of the sol-
vent in vacuo leaves the title compound as a pale yellow
oil (23.6 g., 0.17 mol., 85%), pmr (CDC13) ~ 1.64 (8H,
bs), 2.54 (2H, s), 2.64 (lH, s).
Step A-2: Preparation of 2-[1-(Tetrahydro-2H-pyran-2-yl-
oxy)cyclohexyl]acetonitrile
P-Toluenesulfonic acid hydrate (0.1 g.) is added
to a stirred mixture of 2-(1-hydroxycyclohexyl)aceto-
nitrile ~5.57 g., 40 mmol.) and dihydropyran (3.78 g.,
45 mmol.). As soon as the reaction is initiated (indica-
ted by the temperature rise of the reaction mixture) the
reaction vessel is ~uickly chilled in a cold water bath
and stirring continued for 1.5 hours. The reaction mix-
ture is then diluted with ether, washed with 5% sodium
Z~*S
-21- 16068Y
1 bicarbonate and dried over anhydrous magnesium sulfate~
Evaporation of the solvent in vacuo provides the title
compound as a yellow oil (8.70 g., 39 mmol., 98%), pmr
(CDC13) ~ 2.63 (2H, s), 3.3~ 4.3 (2H, m), 4.87 (lH, m).
Step A-3: Preparation of l-Amino-2-[l-(tetrahydro-2H-
pyran-2-yloxy)cyclohexyl]ethane
An ether (20 ml.) solution of 2-[l-(tetrahydro-
2H-pyran-2-yloxy)cyclohexyl]acetonitrile (8.70 g., 39
mmol.) is added dropwise to a stirred suspension of lith-
ium aluminum hydride (1.292 g., 34 mmol.) in ether (lO0ml.). The resulting mixture is then refluxed for 16
hours. The reaction mixture is cooled to below 5C.,
treated successively with water (1.3 ml.), 15% sodium
hydroxide (1.3 ml.) and then water again (3.9 ml.). The
resulting mixture is stirred at ambient temperature for
30 minutes and the precipitated solid is filtered off.
The filtrate is concentrated in vacuo to yield the title
compound as a pale yellow viscous oil (8.7 g., 38.2 mmol.,
98%), pmr (CDCl3) ~ 2.35 (2H, s, exchangable with D2O),
2.6^~3.0 (lH, m), 3.2~ 4.2 (3H, m), 4.74 (lH, m).
Step B: Preparation of Ethyl 4-~3-[3-[2-(l-Hydroxycyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benz-
oate
Ethyl 4-(4-oxobutyl)benzoate (4.15 g., 18.8
mmol.) is added dropwise to a stirred solution of l-amino-
2-[1-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]ethane in
carbon tetrachloride (l ml.) maintained at 25C. The
resulting mixture is stirred for 30 minutes before being
treated with anhydrous sodium sulfate (4 g.). Stirring
is continued for 2 hours. The solid is removed by filtra-
tion and washed with a small quantity of benzene. The
combined filtrate and washings are diluted with benzene
(7Q ml.), treated with HSCH2CO2H (1.84 g., 20 mmole.) in
one portion, and then refluxed in a Dean-Stark apparatus
~g ~ 5
-22- 16068Y
1 for 16 hours. The reaction mixture is allowed to cool to
room temperature, subsequently washed with diluted hydro-
chloric acid and 5% sodium bicarbonate, dried over anhy-
drous magnesium sulfate, and filtered. Evaporation in
vacuo affords an oil residue which is dissolved in meth-
anol (50 ml.) plus concentrated hydrochloric acid (0.2
ml.). The resulting mixture is stirred at ambient tem-
perature for 3 hours, diluted with water, and extracted
with ether. The ethereal extract i5 washed with diluted
sodium bicarbonate, dried over anhydrous magnesium sul-
fate, filtered, and concentrated to give an oil residue.
The oil residue is then applied to a silica gel column
(120 g.~ with chloroform. Elution with chloroform-
methanol (100:1: v:v; 630 ml.) gives impure material.
Further elution with the same eluant (300 ml.) provides
the title compound (2.5 g., 5.96 mmol., 32%) as a pale
yellow oil, pmr (CDC13) ~ 1.38 (3H, t), 3.50 (2H, s),
4.40 (2H, q), 4.72 (lH, m), 7.23 (2H, d), 8.00 (2H, d).
0 Step C: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl~-4-oxo-2-thiazolidinyl]propyl}benzoic Acid
Sodium hydroxide solution (5N, 2.5 ml., 12.5
mmol.) is added to a stirred mixture of ethyl 4-~3-[3-[2-
(l-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl3-
benzoate (2.48 g., 5.91 mmol.), methanol (25 ml.) andwater (5 ml.). The resulting mixture is stirred at am-
bient temperature for 16 hours. Then, it is diluted with
water, acidified with diluted hydrochloric acid, and ex-
tracted with ether. The ethereal extract is washed with
water, dried over anhydrous magnesium sulfate, and fil-
tered. Upon cooling the filtrate, the title compound
precipitates out as a white solid, which is collected by
filtration (7.06 g., 2.57 mmol., 42%). The product is
recrystallized from chloroform-ether, m.p. 147-148C.,
~.2~2~S
-23- 16068Y
1 ir (KBr) 3320, 1700, 1650 cm 1, pmr (CDC13) ~ 3.54 (2H,
s), 4.70 (lH, m), 7.22 (2H, d), 8.00 t2H, d).
~nal. Calcd. for C21H29NO4S: C, 64.42; H, 7.47; N, 3~58
Found: C, 63.97; H, 7.23; N, 3.40
EXAMPLE 3
Formulations of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl}benzoic Acid
A. Capsule Formulation
4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo
2-thiazolidinyl]propyl}benzoic acid ............ 10 g.
Stearic acid (U.S.P. triple pressure) ............. 125 g.
Pluronic F-68 ..................................... 7.5 g.
Corn Starch ....................................... 125 g.
The stearic acid and pluronic are united in a
vessel and melted using a water bath at 60 to 65C. The
heating is discontinued and the 4-~3-[3-[2-(1-hydroxy-
yclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic acid
is dispersed into the mixture and the corn starch is added
with stirring which is continued until the mixture cools
to ambient temperature. The mixture is reduced to gran-
ules by screening and placed in a number 0 hard gelatin
containing 267.5 mg. of total solids and 10 mg. of 4-~3-
[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-
propyl}benzoic acid per capsule.
~L~.2~Z~S
-24- 16068Y
1 EXAMPLE 4
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid (Alternate Method)
Step A: Preparation of Ethyl 4-[3-(4-oxo-2-thiazolidinyl)-
propyl]benzoate
A mixture of ethyl 4-(4-oxobutyl)benzoate
(24.89 g., 0.113 mole), mercaptoacetamide (30.93 g., 0.339
mole), p-toluenesulfonic acid monohydrate (250 mg.), and
benzene (290 ml.) is heated, under N2, under reflux em-
ploying a Dean-Stark constant water separator for two
hours.
The cooled reaction mixture is poured into water
(600 ml.) and the resulting oil is extracted into ether.
The combined extracts are washed well with water and dried
over anhydrous magnesium sulfate. The solvent is removed
under vacuum to give the title compound as a yellow solid.
After triturating with cyclohexane (75 ml.), there is
obtained 19.70 g., m.p. 97-99C. of white solid. Recry-
stallization from butyl chloride gives white needles,
m.p. 99-100C.
Step B: Preparation of Ethyl 4-~3-[3-(2-(1-Cyclohexenyl)-
ethyl)-4-oxo-2-thiazolidinyl]propyl~benzoate
Ethyl 4-[3-(4-oxo-2-thiazolidinyl)propyl]benz-
oate (14.67 g., 0.05 mole) is dissolved in 35 ml. of 1:1
benzene-DMF and the solution is added dropwise during 30
minutes to a suspension of sodium hydride (1.3 g., 0.055
mole) in 50 ml. of 1:1 benzene-DMF. Temperature is held
at 30C. during the addition by means of a cold water
bath. The mixture is stirred for an additional 15 min-
utes and then treated during 15 minutes with 1-(2-bromo-
ethyl)cyclohexene (10.4 g., 0.055 mole). The mixture is
Z~S
-25- 16068Y
1 then stirred and heated at 55-60C. for 3.5 hours. The
mixture is cooled and poured into 200 ml. of water. The
product is taken up in ether, washed with water, and
dried over MgSO4. Evaporation of solvent at reduced pres-
sure gives 20.5 g. of crude product as an orange viscous
oil.
The crude product is chromatographed on a column
containing 300 g. of silica gel; elution is with chloro-
form followed by 2% methanol in chloroform. Fractions are
combined and evaporated to give two product fractions:
(A) 4.5 g. yellow oil Rf 0.60 with minor impurities at
Rf 0.42 and 0.78 (tlc on SiO2 with 2% methanol in chloro-
form; and (B) 7.8 g., yellow oil, one spot, Rf 0.60. The
combined yield of product used in the next step is 12.3 g.
(61%).
Step C: Preparation of 4-~3-[3-(2-(1-Hydroxycyclohexyl)-
ethyl)-4-oxo-2-thiazolidinyl]propyl}benzoic Acid
A solution of the product of Step B above (3.6
g., 0.009 mole) in trifluoroacetic acid (16 ml.) is
allowed to stand for 4 hours at room temperature. The
solution is then poured into ice-water. The oily product
is taken up in ether and the solution washed with satura-
ted NaHCO3 solution until the washings remain basic. At
the point when excess CF3CO2H has been completely removed,
the oily product separates from the ether solution. It
is redissolved in the organic phase by addition of chloro-
form. The organic solution is then washed with water and
dried over Na2SO4. Evaporation of solvents affords 4.3 g.
of residual brown oil.
This product is dissolved in a solution of
sodium hydroxide (1.2 g., 0.03 mole) in water (10 ml.)
and methanol (40 ml.). The solution is allowed to stand
-26- 16068Y
1 at room temperature for 18 hours. The methanol is dis-
tilled at reduced pressure. The residual solution is
diluted with 50 ml. of water and acidified with concen-
trated hydrochloric acid. The product precipitates as
an oil which quickly crystallizes. It is recrystallized
twice to constant melting point from acetonitrile-water.
There is obtained 1.6 g. (45%) of 4-~3-[3-(2-(1-hydroxy-
cyclohexyl)ethyl)-4-oxo-2-thiazolidinyl]propyl~benzoic
acid, m.p. 147-148C.
ExAMæLE 5
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid (Alternate Method)
Step A: Preparation of 4-~3-[3-[2-(1-Cyclohexenyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A solution of ethyl 4-~3-[3-[2-(1-cyclohexenyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate (Example 4,
Step B) (4.0 g., 0.01 mole) and sodium hydroxide (1.2 g.,
0.003 mole) in methanol (50 ml.) and water (5 ml.) is
allowed to stand at 25C. for 18 hours~ The methanol is
distilled at reduced pressure. The residual solution is
treated with water (50 ml.) and acidified with 2N hydro-
chloric acid. The title compound precipitates as an oil
that gradually crystallizes. It is collected, washed
with water, and air dried.
Step B: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A solution of 4-~3-[3-[2-(1-Cyclohexenyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl~benzoic acid (3.7 g., 0.01
mole) in trifluoroacetic acid (20 ml.) is allowed to
stand at 25C. for 4 hours. Excess trifluoroacetic acid
~ 'h4Z~S
-27- 16068Y
1 is then removed by evaporation at reduced pressure. The
oily residue is dissolved in a solution of sodium hydrox-
ide (2.0 g., 0.05 mole) in water (40 ml.). The basic
solution is acidified with 2N hydrochloric acid. The
title compound precipitates as a solid. Recrystalliza-
tion from acetonitrile-water yields the purified title
compound, m.p. 147-148C.
EXAM2LE 6
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-
1,4-dioxo-2-thiazolidinyl]propyl~benzoic Acid
Sodium metaperiodate (0.75 g., 3.5 mmoles) is
added to a cold (0-5C.) solution of 4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~-
benzoic acid (1.33 g., 3.4 mmoles) in methanol (20 ml.)
and water (5 ml.). The resulting mixture is stirred
without further cooling for 16 hours. The precipitated
solid is then removed by filtration. The filtrate is
diluted with water and extracted with chloroform. The
organic extract is washed with brine, dried over sodium
sulfate, and evaporated in vacuo to leave an oily residue
which is chromatographed on silica gel (25 g.). Elution
with 4% acetic acid in chloroform affords the title com-
pound as a viscous, yellowish oil.
EXAMPLE 7
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-
1,1,4-trioxo-2-thiazolidinyl]propyl~benzoic Acid
A mixture of 4-~3-[3-[2-(1-hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic acid (0.391
g., 1.0 mmol.), m-chloroperoxybenzoic acid (100%, 0.362
g., 2.1 mmol.), and chloroform (5 ml.) is refl~xed for
~.2~2~5
-28- 16068Y
1 30 minutes. The reaction mixture is evaporated ln vacuo
to give a solid residue which is applied to a silica gel
column (18 g.) with chloroform. Elution with chloroform-
acetic acid (25:1; v:v; 150 ml.) provides m-chlorobenzoic
acid and impure material. Continued elution with the
same eluant affords the title compound as a colorless
viscous oil (0.273 g., 0.64 mmol., 64%), pmr ~CDC13) S
3.75 ~2~, s), 4.60 ~lH, m), 7.26 (2H, d), 8.00 (2H, d).
EXAMPLE 8
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl}-2-chlorobenzoic Acid
Step A: Preparation of Ethyl 2-chloro-4-(4-oxobutyl)-
benzoate
.
This compound is prepared by the same series of
reactions described in Example 1, Step A, for the prepara-
tion of ethyl 4-(4-oxobutyl)benzoate except that, in Step
A-l, 2-chloro-4-methylbenzoic acid is substituted for p-
toluic acid. There is thus obtained in Step A-l of this
example, ethyl 2-chloro-4-~3-[2-(1,3-dioxolanyl~propyl}-
benzoate, b.p. 165-170C. (0.1 mm.), and in Step A-2,
ethyl 2-chloro-4-(4-oxobutyl)benzoate.
Step B: Preparation of Ethyl 3-Chloro-4-[3-(4-oxo-2-
thiazolidinyl)pro~yl]benzoate
This compound is prepared by the method de-
scribed in Example 4, Step A, except that an equivalent
quantity of ethyl 2-chloro-4-(4-oxobutyl)benzoate is sub-
stituted for the ethyl 4-(4-oxobutyl)benzoate of Example
4, Step A. The title compound is obtained as white
needles (from butyl chloride), m.p. 81.5-82.5~C.
Anal. Calc'd for C15H18ClNO3S: C, 54.96; H, 5.53; N, 4.27
Found: C, 55.29; H, 5.64; N, 4.31
~z'~s
-29- 16068Y
1 Step C: Preparation of Ethyl 2-Chloro-4-~3-[3-[2-(1-
Cyclohexenyl)ethyl]-4-oxo-2-thiazolidinyl]prop-
yl~benzoate
This compound is prepared by the method de-
scribed in Example 4, Step B, except that an equivalent
quantity of ethyl 2-chloro-4-[3-(4-oxo-2-thiazolidinyl)-
propyl]benzoate is substituted for the ethyl 4-[3-(4-oxo-
2-thiazolidinyl)propyl]benzoate of Example 4, Step B.
The title compound is obtained as an oil by column chro-
matography on silica gel with 2% methanol in chlorofoxmas eluant.
Step D: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl)-4-oxo-2-thiazolidinyl]propyl}-2-chloro-
benzoic Acid
This compound is prepared by the method de-
scribed in Example 4, Step C, except that an equivalent
quantity of ethyl 2-chloro-4-~3-[3-[2-(1-cyclohexenyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate is substi-
tuted for the ester employed in Example 4, Step B. The
title compound is obtained as an amorphous solid, m.p.
104-108C.
EXAMPLE 9
Preparation of 3-{3-[3-[2-~(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid
Step A-l: Preparation of Ethyl 3-(1-Propenyl)benzoate
(3-Methoxycarbonylbenzyl)triphenylphosphonium
bromide (54.1 g., 0.11 mole) is suspended with stirring
in a mixture of acetaldehyde (5.8 g., 0.132 mole) and
ethanol (250 ml.). A solution of sodium (2.5 g., 0.11
~.z~2r~5
_30_ 1606
1 mole) in ethanol (300 ml.) is added dropwise during 30
minutes. The reaction mixture is stirred an additional
4 hours at room temperature and then concentrated to
about 1/4 volume at reduced pressure. Water (150 ml.)
is added to the residue, and the oily product taken up in
ether and dried over magnesium sulfate. Ether is evapor-
ated. The residue is treated with 100 ml. of petroleum
ether. Insoluble triphenylphosphine oxide is filtered
off, and the filtrate distilled ln vacuo to yield 14.0 g.
(72%) of ethyl 3-(1-propenyl)benzoate, b.p. 85-87C. (0.1
mm.). Note that the product is an ethyl ester as a result
of transesterification with solvent ethanol during the
reaction.
Step A-2: Preparation of Ethyl 3-(3-Bromo-l-propenyl)-
benzoat~e
A mixture of ethyl 3-(1-propenyl)benzoate (14.0
~., 0.074 mole~, N-bromosuccinimide (14.9 g., 0.084 mole),
benzoyl peroxide (150 mg.), and carbon tetrachloride (75
ml.~ is stirred and heated at reflux for 46 hours. The
mixture is cooled. Solids are filtered off, and the fil-
trate is washed with water and dried over magnesium sul-
fate. The solvent is evaporated, and the residual oil
distilled to yield 10.2 g. (51%) of ethyl 3-(3-bromo-1-
propenyl)benzoate, b.p. 129-131C. (0.05 mm.).
Step A-3: Preparation of Ethyl 3-(4-Oxo-l-butenyl)benz-
oate
Methyl methylthiomethyl sulfoxide (12.4 g., 0.1
mole) is added dropwise during 30 minutes to a stirred
suspension of sodium hydride (2.4 g., 0.1 mole) in tetra-
hydrofuran (100 ml.). Then, ethyl 3-(3-bromo-1-propenyl)-
benzoate (26.9 g., 0.1 mole) is added in one portion, and
the mixture is stirred at 30C. for 2 hours and at 45-
50C. for 2 hours. The solvent is evaporated in vacuo.
42~S
-31- 16068Y
1 The residue is treated with water, and the oily product is
taken up in ether and dried over sodium sulfate. Evapora-
tion of the ether affords the dimethyl mercaptal S-oxide
of the title aldehyde. This material is dissolved in 200
ml. of tetrahydrofuran with 5 ml. of 10% hydrochloric acid
and the resulting solution is refluxed for 2 hours. The
solvent is evaporated, and the residue is taken up in
ether, washed with water, and dried over sodium sulfate.
Evaporation of the solvent in vacuo affords the title
aldehyde as a mobile oil which is used immediately in the
next step.
Step B: Preparation of Ethyl 3-~3-[3-[2-(1-Hydroxycyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propenyl}benz-
oate
This compound is prepared by the method de-
scribed in Example 2, Step B, except that an equivalent
amount of ethyl 3-~4-oxo-1-butenyl)benzoate is substituted
for ethyl 4-(4-oxobutyl)benzoate. The title compound is
obtained as a viscous, yellow oil.
Step C: Preparation of 3-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propenyl}benzoic
Acid
This compound is prepared by the method de-
scribed in Example 2, Step C, except that an equivalent
quantity of the ester obtained in Step B is sub]ected to
hydrolysis. The title compound is obtained as a viscous,
yellow oil after purification by chromatography on silica
gel with 2% methanol in chloroform elution.
Step D: Preparation of 3-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl7benzoic Acid
3-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propenyl~benzoic acid (7.8 g., 0.02 mole)
in e~hanol (125 ml.) is hydrogen~ted over 2.5 g. of a 5
2~S
-32- 16068Y
1 Pd on charcoal catalyst at 1 atmosphere pressure and 27C.
When the theoretical amount (0.02 mole) of hydrogen has
been absorbed, the catalyst is filtered off, the solvent
evaporated, and the residue chromatographed on silica gel
with 4% methanol in chloroform as the eluant. The title
compound is obtained as a colorless, viscous oil.
EXAMPLE 10
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-
5,5-dimethyl-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
Step A: Preparation of Ethyl 4-~3-[3-[2-(1-Hydroxycyclo-
hexyl)ethyl]-5,5-dimethyl-4-oxo-2-thiazolidinyl]-
~ro~vl~benzoate
_
A solution of ethyl 4-(4-oxobutyl)benzoate (5.5
g., 0.025 mole) and 1-(2-aminoethyl)cyclohexanol (3.7 g.,
0.026 mole) in toluene (40 ml.) is boiled in an open
flask for 5 minutes to remove the formed water as the
azeotrope. 2-Mercapto-2-methylpropionic acid (3.3 g.,
0.0275 mole) is added and the solution is boiled under a
Dean-Stark water separator for 5 hours. The solution is
then cooled, washed with 2N hydrochloric acid and water,
and dried over sodium sulfate. The solvent is removed at
reduced pressure. The residue is chromatographed on 165
g. of silica gel with 2% methanol in chloroform as the
eluent. There is obtained 4.6 g. of the title ester as
a light yellow, viscous oil.
Step B: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-5,5-dimethyl-4-oxo-2-thiazolidinyl]prop-
y17benzoic Acid
. ~
The product of Step A above is saponified
exactly as described in Example 2, Step C, to yield the
title product as a crystalline solid, m.p. 132-137C.
(from acetonitrile-water).
s
-33- 16068Y
1 ExAMæLE 11
Preparation of 4-~3-[3-[2-~1-Hydrox~cyclopentyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid
This compound is prepared by the method de-
scribed in Example 2, except that an equivalent quantity
of cyclopentanone is substituted for the cyclohexanone
employed in Example 2, Step A-l. There are thus obtained
in the corresponding steps of this example:
Step A-l: 2-(1-hydroxycyclopentyl)acetonitrile;
10 Step A-2: 2-[1-(tetrahydro-2H-pyran-2-yloxy)cyclopent-
yl]acetonitrile;
: l-amino-2-[1-(tetrahydro-2H-pyran-2-yloxy)-
cyclopentyl]ethane;
Step B: ethyl 4-~3-[3-[2-(1-hydroxycyclopentyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl~benzoate; and
Step C: 4-~3-[3-[2-(1-hydroxycyclopentyl)ethyl]-4-oxo-
2-thiazolidinyl]propyl~benzoic acid.
The last named product of this invention is
obtained as a crystalline solid, m.p. 149-150~C. (from
acetonitrile).
EXAMPLE 12
Preparation of 4-~3-[3-[2-(1-Hydroxycycloheptyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl~benzoic Acid
This compound is prepared by the method de-
scribed in Example 2, except that an equivalent quantity
of cycloheptanone is substituted for the cyclohexanone
employed in Example 2, Step A-l. There are thus obtained
in the corresponding steps of this example:
Step A-l: 2-(1-hydroxycycloheptyl)acetonitrile;
-34- 16068Y
1 Step A-2: 2-[l-(tetrahydro-2H-pyran-2-yloxy)cycloheptyl]
acetonitrile;
Step A-3: 1-amino-2-[1-(tetrahydro-2H-pyran-2-yloxy)-
cycloheptyl]ethane;
Step B: ethyl 4-~3-[3-[2-(1-hydroxycycloheptyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoate; and
Step C: 4-~3-[3-[2-(1-hydroxycycloheptyl)ethyl]-4-oxo-
2-thiazolidinyl]propyl~benzoic acid.
The last named product of this invention is
obtained as a crystalline solid, m.p. 146.5-147.5C.
(from acetonitrile).
EXAMPLE 13
Preparation of 4-~3-[3-[2-(1-Hydroxy-4,4-dimethylcyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinvl]propyl~benzoic Acid
This compound is prepared by the method de-
scribed in Example 2, except that an equivalent quantity
of 4,4-dimethylcyclohexanone is substituted for the cyclo-
hexanone employed in Example 2, Step A-l. There are thus
obtained in the corresponding steps of this example:
Step A-l: 2-(1-hydroxy-4,4-dimethylcyclohexyl)aceto-
nitrile;
Step A-2: 2-[1-(tetrahydro-2H-pyran-2-yloxy)-4,4-dimeth-
ylcyclohexyl]acetonitrile;
_ep A-3: 1-Amino-2-[1-(tetrahydro-2H-pyran-2-yloxy)-
4,4-dimethylcyclohexyl]ethane;
Step B: Ethyl 4-~3-[3-[2-(1-hydroxy-4,4-dimethylcyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benz-
oate; and
2~LS
-35- 16068Y
1 Step C: 4-~3-[3-[2-(1-hydroxy-4,4-dimethylcyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic
Acid.
The last named product of this invention is
obtained as a crystalline solid, m.p. 142-143C. (from
acetonitrile).
EXAMPLE 14
Preparation of 4-~3-[3-[2-(4-Hydroxytetrahydro-4-thio-
pyranyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
This compound is prepared by the method de~
scribed in Example 2, except that an equivalent quantity
of tetrahydrothiopyran-4-one is substituted for the cyclo-
hexanone employed in Example 2, Step A-l. There are thus
obtained in the corresponding steps of this example:
Step A-l: 2-(4-hydroxytetrahydro-4-thiopyranyl)aceto-
nitrile;
Step A-2: 2-[4-(tetrahydro-2H-pyran-2-yloxy)-tetrahydro-
4-thiopyranyl]acetonitrile;
Step A-3: 1-Amino-2-[4-(tetrahydro-2H-pyran-2-yloxy)-
tetrahydro-4-thiopyranyl]ethane;
Step B: Ethyl 4-~3-[3-[2-(4-hydroxytetrahydro-4-thio-
pyranyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benz-
oate; and
Step C: 4-~3-[3-[2-(4-hydroxytetrahydro-4-thiopyranyl)-
ethyl]-4-oxo-2-thiaæolidinyl]propyl~benzoic Acid.
The last named product of this in~ention is
obtained as a crystalline solid, m.p. 157 157.5C. (from
acetonitrile).
-36- 16068Y
1 EXAMPLE 15
Preparation of 4-~3-[3-[2-(4-Hydroxytetrahydro-4-pyran-
yl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic Acid
This compound is prepared by the method de-
scribed in Example 2, except that an equivalent quantityof tetrahydropyran-4-one is substituted for the cyclo-
hexanon~ employed in Example 2, Step A-l. There are thus
obtained in the corresponding steps of this example:
Step A-l: 2-(4-hydroxytetrahydro-4-pyranyl)acetonitrile;
Step A-2: 2-[4-(tetrahydro-2H-pyran-2-yloxy)-tetrahydro-
4-pyranyl]acetonitrile;
Step A-3: 1-Amino-2-[4-(tetrahydro-2H-pyran-2-yloxy)-
tetrahydro-4-pyranyl]ethane;
Step B: Ethyl 4-~3-[3-[2-(4-hydroxytetrahydro-4-pyranyl-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate; and
Step C: 4-~3-[3-[2-(4-Hydroxytetrahydro-4-pyranyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl~benzoic acid.
EXAMPLE 16
Preparation of 4-~3-[3-[2-(9-Hydroxy 9-bicyclo[3.3.1]non-
yl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
This compound is prepared by the method de-
scribed in Example 2, except that an equivalent quantity
of bicyclo[3.3.1]nonan-9-one is substituted for the cyclo-
hexanone employed in Example 2, Step A-l. There are thus
obtained in the corresponding steps of this example:
Step A-l: 2-(9-hydroxy-9-bicyclo[3.3.1]nonyl)aceto-
nitrile;
Step A-2: 2-[9-(tetrahydro-2H-pyran-2-yloxy~-9-bicyclo~
[3.3.1]nonyl]acetonitrile;
~.Z~2~5
-37- 16068Y
1 Step A-3: 1-amino-2-[9-ttetrahydro-2H-pyran-2-yloxy)-9-
bicyclo[3.3.1]nonyl]ethane;
Step B: Ethyl 4-~3-[3-[2-(9-hydro-9-bicyclo[3.3.1]nonyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate; and
Step C: 4-~3-[3-[2-(9-hydroxy-9-bicyclo[3.3.1]nonyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid.
The last named product of this invention is
obtained as a crystalline solid, m.p. 176.5-178C. (from
acetonitrile).
_XAM2LE 17
Preparation of 4-~3-[3-[3-(1-Hydroxycyclohexyl)-2-propyn-
yl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
Step A: Preparation of Ethyl 4-~3-[3-[3-(1-Acetoxycyclo-
hexyl)-2-propynyl]-4-oxo-2-thiazolidinyl]propyl~-
benzoate
This compound is prepared by the alkylation
procedure described in Example 4, Step B, except that an
equivalent quantity of l-acetoxy-l-(3-bromo-1-propynyl)-
cyclohexane is substituted for the l-(2-bromoethyl)-
cyclohexene used in Example 4, Step B. The title product
is obtained as a yellowish viscous oil in 85~ yield after
chromatography on silica gel.
Step B: Preparation of 4-~3-[3-[3-(1-Hydroxycyclohexyl)-
2-propynyl]-4-oxo-2-thiazolidinyl]propyl~benzoic
Acid
The ester obtained in Step A above is saponi-
fied by the method described in Example 2, Step C. The
crystalline product is purified by recrystallization from
acetonitrile-butyl chloride, m.p. 112-115C.
~.Z~5
-38- 16068Y
1 ExAMæLE 18
Preparation of 4-~3-[3-[3-(1-Hydroxycyclohexyl)-(Z)-2-
propenyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
4-~3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic acid (4.0 g., 0.01
mole) is dissolved in ethyl acetate (50 ml.) and hydrog-
enated at 25C. and one atmosphere pressure over 1.0 g.
of a 5% palladium on charcoal catalyst. The theoretical
amount (0.01 mole) of hydrogen is absorbed in 110 minutes.
The catalyst is removed by filtration and the solvent
evaporated. The residual oil is chromatographed on 60 g.
of silica gel with elution by 2% methanol in chloroform.
The chromatographed product crystallizes and is recrys-
tallized from butyl chloride to yield 1.4 g. of the title
product, m.p. 118-120C.; pmr (CDC13) ~ 5.14 (lH, m,
-CH2-CH=), 5.60 (lH, d, J=12Hz -CH-C-~H).
_
EXAMPLE 19
Preparation of 4-~3-[3-[3-(1-Hydroxycyclohexyl)propyl]-
4-oxo-2-thiazolidinyl]propyl~benzoic Acid
4-~3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-
oxo-2-thiazolidinyl]propyl}benzoic Acid (4.0 g., 0.01
mole) is dissolved in ethyl acetate (45 ml.) and hydrog-
enated at 25C. and one atmosphere pressure over 1.0 g.
of a 5% palladium on charcoal catalyst. When 0.01 mole
of hydrogen is absorbed (2 hours), uptake of hydrogen
becomes very slow. An additional 1.5 g. of catalyst is
added and hydrogenation continued for 70 hours until
0.02 mole of hydrogen has been absorbed. The catalyst
is removed by filtration and the solvent evaporated.
The residual oil is chromatographed on silica gel with
Z L yL 5
-39- 16068Y
1 elution by 2% methanol in chloroform. The chromato-
graphed product crystalizes when triturated with ether.
There is obtained 1.2 g. of the title product, m.p. 118-
121C.
EXAMPLE 20
Preparation of 4~3-[3-[3-~1-Hydroxycyclohexyl)-(E)-2-
propenyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
Step A-l: Preparation of (E)-1-(3-Diethylamino-l-propen-
yl)cyclohexanol
A stirred suspension of lithium tetrahydrido-
aluminate (1.13 g., 0.0299 mole) in ether (25 ml.) under
N2 is cooled in an ice bath to 0C. and treated, drop-
wise, during 30 minutes, with a solution of 1-(3-diethyl-
amino-l-propynyl)cyclohexanol (5.00 g., 0.0239 mole) in
ether (5 ml.), while temperature is maintained 0-5C.
After addition is complete, the cooling bath is removed
and stirring is continued for 3 hours. The mixture is
again cooled in an ice bath and the excess lithium tetra-
hydridoaluminate is decomposed by the cautious addition
of saturated ammonium chloride solution (30 ml.). The
mixture is filtered and the collected semi-solid is washed
well with ether. The combined filtrate and washings are
washed well with water and dried over anhydrous magnesium
sulfate. The solvent is removed under vacuum to give the
title compound as a yellow residual oil, yield 3.41 g.;
pmr (CDC13) ~ 5.73 (2H, m. CH=CH).
Step A-2: Preparation of (E)-1-(3-Chloro-l-propenyl)-
cvclohexanol
(E)-1-(3-Diethylamino-l-propenyl)cyclohexanol
(23.4 g., 0.11 mole) and potassium carbonate (1.0 g.) are
added to ether (200 ml~). The mixture is stirred and
~ ~f, Z L~h~ t~ 5
-40- 16068Y
1 treated dropwise during 30 minutes with a solution of
ethyl chlorocarbonate (13.1 g., 0.12 mole) in ether (30
ml.). The reaction mixture is stirred for 18 hours at
25C. It is then washed with 2N hydrochloric acid and
water, and dried over sodium sulfate. Vacuum distilla-
tion yields 11.7 g. of ethyl N,N-diethylcarbamate, b.p.
45-50C. (0.25 mm) and 7.4 g. of (E)-1-(3-chloro-1-pro-
penyl)cyclohexanol, b.p. 88-90C. (0.25 mm.); pmr (CDC13)
~ 4.04 (2H, m, CH2Cl), 5.80 (2H, m, CH=CH).
Step A-3: Preparation of (E)-1-(3-Chloro-l-propenyl)-1-
(tetrahydro-2H-pyran-2-yloxy)cyclohexane
A solution of (E)-1-(3-chloro-1-propenyl)cyclo-
hexanol (6.1 g., 0.035 mole), dihydropyran (4.6 g., 0.055
mole) and pyridinium tosylate ~0.5 g.) in dichloromethane
(30 ml.) is kept at 25C. for 3.5 hours. The solution is
washed with saturated sodium bicarbonate solution and
water, and dried over sodium sulfate. Evaporation of the
solvent at reduced pressure vields 9.0 g. of the title
product as a yellowish oil which is used in the next step
without further purification.
Step B: Preparation of Ethyl 4-~3-[3-[3-(1-(Tetrahydro-
2H-pyran-2-yloxy)cyclohexyl)-(E)-2-propenyl]-4-
oxo-2-thiazolidinyl]propyl~benzoate
This compound is prepared by the alkylation
procedure described in Example 4, Step B, except that an
equivalent quantity of (E)-1-(3-chloro-1-propenyl)-1-
(tetrahydro-2H-pyran-2-yloxy)cyclohexane is substituted
for the l-(2-bromoethyl)cyclohexene used in Example 4,
Step B. The title product is obtained as a yellow, vis-
cous oil after chromatography on silica gel.
~.Z~ .5
-41- 16068Y
1 Step C: Preparation of 4-~3-~3-[3-(1-Hydroxycyclohexyl)-
(E)-2-propenyl]-4-oxo-2-thiazolidinyl]propyl~-
benzoic Acid
A solution of the ester product of Step B above
(4.5 g., 8.7 mmole) and pyridinium tosylate (220 mg.,
0.87 mmole) in ethanol (50 ml.) is let stand at 25C. for
2.5 hours. To this reaction solution is added a solution
of sodium hydroxide (1.2 g., 30 mmole) in water (12 ml.).
The resulting solution is let stand at 25C. for 20 hours
The ethanol is then evaporated at reduced pressure. The
residue is dissolved in water, and the solution acidified
with 2N hydrochloric acid to precipitate the product as a
yellow gum. It is chromatographed on 60 g. of silica gel
with elution by 2~ methanol in chloroform. The purified
title product is obtained as a yellowish, viscous oil
weighing 2.4 g~; pmr (CDC13) ~ 2.74 (2H, brt, CH2Ph),
3.55 (2H, brs, COCH2S), 4.70 (lH, brd, SCHN), 5.70 (2H,
m, CHzCH), 6.53 (2H, brs, OH and C02H).
EXAMPLE 21
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-
5,5-dideuterio-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A solution of 4-~3-[3-[2-(1-hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (391 mg.
1~0 mmole) and sodium hydroxide (160 mg., 4.0 mmoles) in
deuterium oxide (5 ml.) is allowed to stand at 25C. for
24 hours. The solution is acidified with 2N hydrochloric
acid to precipitate the crystalline product. This mater-
ial is collected, washed with water, and air dried.
There is obtained 288 mg. of the title compound, m.p.
146.5-14~C.
The absence of the 2- proton signal at ~ 3.54
in the pmr spectrum shows that two deuterium atoms have
been placed in the 5-position of the ~hiazolidinone ring.
2~S
- -42- 160~8Y
lAdditional Processes
. .
DESCRIPTION OF THE INVENTION
This invention also relates to other alternate
processes for the preparation of ~-~3~[3-[2-(l-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic
acid of formula IA:
r ~ , COOH
O HO
.
It is an object of the present invention to
provide new processes for the preparation of 4-~3-[3-[2-
(l-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]prop-
yl~benzoic acid by elaboration of the propyl benzoic acidside chain of the thiazolidinone ring.
It is a further object of the present invention
to provide new processes for the preparation of compound
IA by the elaboration of a hydr~xycyclohexylethyl side
chain in the three position of a thiazolidinone ring.
It is a still further object of the present
invention to provide new processes for the preparation of
compound IA by the elaboration of a thiazolidinone ring
in a compound having a preformed hydroxycyclohexylethyl
side chain attached to nitrogen and a preformed propyl
benzoic acid side chain attached to a carbon atom imme-
diately adjacent to said nitrogen atom.
The followiny processes are methods for elabora-
tion of the propyl benzoic acid side chain.
~,
z~
~43~ 16068Y
1 One group of these processes involves the pre-
paration of IA by the hydrolysis of suitable functional
groups to produce the carboxy group which is characteris-
tic of that substance.
One such process involves the preparation of
IA by the hydrolysis in the presence of base of precursox
amides. Such amides may be either primary, secondary, or
tertiary. The reaction media consist of a suitable
strong base (e.g., sodium hydroxide, potassium hydroxide,
lithium hydroxide) in solution in a mixture of water and
some other solvent to provide miscibility; for example,
methanol ethanol, glycol, tetrahydrofuran, or dioxane.
Temperatures of hydrolyses xange from 50 to 100C.
Times of reaction range from 24-72 hours.
Another such process produces compound IA via
the hydrolysis of a carboxylic acid precursor nitrile.
The hydrolysis can be carried out with bases like sodium
or potassium hydroxide, or lithium hydroxide in aqueous
media. Co-solvents li~e methanol, ethanol, tetrahydro-
furan, or dioxane may be added. The temperature ranges
are 0 to 100C. ~he reaction times are 1 hour to 48
hours.
Another such process involves the preparation
of compound IA by the basic hydrolysis of iminoester
hydrochloride precursors. These precursors have the
formula:
NH.HCl
~S ~ C-O-R
~ N ~
HO V
wherein R is lower alkyl.
~Lz~s
-44_ 16068Y
l The hydrolyses are carried out in mixtures of
water and lower alcohols such as methanol or ethanol.
Bases advantageously employed are sodium, potassium, or
lithium hydroxide usually in a ratio of 3 to 6 moles per
mole of iminoester hydrochloride. Useful temperature
ranges are from 25-75C. and reaction times from 24-72
hours.
Another such process involves the preparation
of compound IA by the basic hydrolysis of thioiminoester
hydrochloride precursors. These precursors have the
formula:
NH.HCl
C-S-R
O HO
wherein R is lower alkyl.
- The hydrolyses are carried out in mixtures of
water and lower alcohols such as methanol or ethanol.
Bases advantageously employed are sodium, potassium, or
lithium hydroxide usually in a ratio of 3 to 6 moles per
mole of thioiminoester hydrochloride. Useful temperature
ranges are from 25-75C. and reaction times from 24-72
hours.
Another such process is the hydrolysis of an
oxazoline moiety, which is a latent carboxy group, for
example:
~2~ > ~ COO~
The oxazoline moiety can be hydrolyzed to com-
pound IA with strong acids such as sulfuric, hydrochloric,
~.Z~5
~45~ 16068Y
1 or trifluoroacetic acid in water or aqueous methanol or
ethanol. The hydrolysis is carried out between 0 and
30C~ from 1 hour to 24 hours.
Another such process includes the preparation
of IA by hydrolysis of a selenyl ester in the presence
of mercuric chloride. Reaction time is 0.5 to 3 hours.
The temperature range is 0 to 65C. Suitable reaction
media are tetrahydrofuran or acetonitrile with calcium
or cadmium carbonates.
Another such process is the acid-catalyzed
hydrolysis of alkyl esters of IA. Such hydrolyses are
carried out in mixtures of water and a solvent to give
miscibility such as a lower alkanol, acetic acid, diox-
ane, or tetrahydrofuran, and in the presence of a strong
acid such as sulfuric or hydrochloric acid. Reaction
temperatures range from 25 to 95C. and times from one
to twelve hours.
Also included are alkaline hydrolyses of lower
alkyl esters of compound IA described in more detail in
present Examples 1, 2, and 3.
Another group of processes for elaboration of
the propylbenzoic acid side chain of IA includes non-
hydrolytic cleavages of suitable functional groups to pro-
duce the carboxy group.
One such process involves the preparation of
IA by the hydrogenolysis of the arylmethyl esters thereof.
Such esters are most advantageously the benzyl, substitu-
ted benzyl, and benzhydryl esters. A palladium catalyst
is employed which may be combined with charcoal as a
supporting substance. Solvents may be alcohols such as
methanol or ethanol or non-protic substances such as
ethyl acetate or dioxane. Hydrogen pressures of from one
z~s
-46- 16068Y
1 to four atmospheres are employed. Reaction temperatures
may range from 25 to 60C. The reactions are continued
until the theoretical amount of hydrogen is absorbed.
Another such process involves preparation of
compound IA by non-hydrolytic cleavage of cinnamyl ester
precursors. This is a two-step process, but the inter-
mediate product of the first step is not isolated, ren-
dering the process functionally one-step.
The first phase of the process is the addition
of a mercuric salt, preferably mercuric acetate, to the
double bond of the cinnamyl ester. This phase is con-
ducted in methanol or ethanol with a catalytic amount of
a strong acid (e.g., nitric acid). Temperatures of 15-
35C. are employed and reaction times range from 2-6
hours. The first phase is terminated by adding sodium
or potassium bicarbonate and evaporating the solvent at
reduced pressure.
The second phase (demercuration-elimination)
consists of stirring the residual mercurial with cyclo-
hexane and an aqueous solution of 8-12 equivalents of
sodium or potassium thiocyanate. This phase is conducted
at 15-40C. for 12-48 hours. The acid product of cleav-
age is precipitated when the reaction mixture is acidi-
fied.
Another process involves a non-hydrolytic
cleavage of lower alkyl esters by treating such esters
with trimethylsilyl iodide in chloroform or carbon tetra-
chloride. The reaction time is 1 to 48 hours. Reaction
temperatures range from 30 to 65C.
Another such process involves the preparation
of compound IA via the pyrolysis of a t-butyl ~ster. The
reaction can be carried out in hydrocarbon solvents like
~2~5
-47- 16068Y
1 xylenes or benzene at their respective boiling points.
The reaction is aided by the addition of an acid catalyst
like trifluoroacetic acid, p-toluene sulfonic acid, or
camphor sulfonic acid.
Another such process includes a non-hydrolytic
ester cleavage via the reductive elimination of a ~-(tri-
methylsilyl)ethyl ester using tetrabutylammonium fluoride.
The reaction is carried out at 10 to 60C. in solvents
such as dimethyl sulfoxide, tetrahydrofuran, or dioxane
and under anhydrous conditions. The reaction time varies
from instantaneous to 5 hours. An alternate source of
fluoride ion to effect cleavage of the ester can be used
such as potassium fluoride in the presence of 1,4,7,10,
13,16-hexaoxacyclooctadecane in an appropriate solvent
such as tetrahydrofuran or diethyl ether.
Another such process includes the reductive
elimination of a 2,2,2-trihaloethyl ester with metallic
zinc in solvents such a3 methanol, ethanol, or aqueous
acetic acid. The halide can be chloro or bromo. The
temperature range is from 25 to 70C. and the reaction
time is from 0.5 to 36 hours.
Another such process includes the preparation
of compound IA by the cleavage of a methylthiomethyl-
ester. The ester can be removed under non-aqueous con-
ditionsj e.g., trifluoroacetic acid, at temperaturesranging from 0C. to 50C., using a reaction time of
0.25 to 2 hours. Alternatively, it can be cleaved in a
solution of acetone-water containing methyl iodide. The
reaction time varies from 10 hours to 24 hours at tem-
perature ranges from 23C. to 100C.
Another such process describes the preparationof IA via the reductive cleavage of a corresponding
2~5
-48- 16068Y
1 2-anthraquinomethyl ester by an electron transfer process.
The reaction is carried out in solvents like dimethyl-
formamide, hexamethylphosphoric triamide, or N-methyl-
pyrrolidone at temperatures of 15 to 30C. The reaction
time is 1 to 36 hours using bases such as triethylamine
or other tertiary amines like diisopropylethylamine. The
electron transfer reagent can be anchored on a solid sup-
port like a polystyrene resin functionalized with 9,10-
dihydroxyanthracene residues. The cleavage of the ester
can also be carried out using sodium dithionite (~ eq.)
in water-dioxane or via photolysis of the ester (at 350
nm.) in isopropanol containing N-methylmorpholine.
Another such process includes the oxidative
cleavage of the hydrazide of compound IA. The reaction
can be carried out in ace~onitrile, tetrahydrofuran, or
dioxane, with water as co-solvent at a temperature range
of 0C. to 40C. for a period of 0.5 to 5 hours. The
oxidizing agent advantageously is ceric ammonium nitrate.
Another such process includes the reductive
elimination of a 2-p-toluenesulfonyl ethyl to give com-
pound IA. The elimination is carried out with strong
bases like 1,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diaza-
bicyclo[5.4.0]undec-5-ene, diisopropylethylamine, or
tetramethylpiperidine in aprotic solvents like benzene,
toluene, or tetrahydrofuran at 0C. to 110C. for 1 hour
to 12 hours. Alternatively, alcoholic sodium or potassium
hydroxide in ethanol or isopropanol at 0C. to 100C. can
also effect hydrolysis via elimination.
Another such process includes the non-hydrolytic
cleavage of a benzyl ester of compound IA using sodium or
potassium thiocyanate in solvents such as dimethylforma-
mide, hexamethylphosphoric triamide, or N-methylpyrroli-
done. Temperatures range from 23 to 170C. and the re-
action times vary from 1 to 18 hours.
~.Z~Z'~5
~49~ 16068Y
1 Another such process for the preparation of
compound IA includes the controlled potential electrol-
ysis of a ~-haloester. Solvents which may be used are
alcohols, dimethylformamide, and acetonitrile within a
temperature range from 0C. to 15C. A proton source
like acetic or trifluoroacetic acid may be added. The
inert electrolyte may also be changed to include lithium
acetate or lithium chloride or similar substances. The
reaction times vary from 1 hour to 5 hours.
Another such process for the preparation of
compound IA includes the non-hydrolytic cleavage of an
anthryl ester. The reaction uses sodium or potassium
methyl- or ethylmecaptide in dimethylformamide or hexa-
methylphosphoric triamide at -25 to 30C. The reaction
time is within the limit of 30 seconds to 6 hours.
Another process for the preparation of compound
IA is the non-hydrolytic ester cleavage of the methyl
ester precursor of IA using lithium iodide as the reagent.
Solvents like 2,4,6-collidine, dimethylformamide, or N-
methylpyrrolidinone may be employed. The preferred tem-
perature is the boiling point of the solvent used. The
reaction is specific for methyl esters.
Other processes for elaborating the propyl-
benzoic acid side chain of compound IA include the fol-
lowing methods.
One process involves preparation of IA by thecatalytic hydrogenolysis of precursors with one or more
halogen substituents on the benzene ring. The halogen
substituents may be chlorine, bromine, or iodine. The
catalyst is palladium which may be combined with charcoal
as a supporting substance. A solvent is employed which
may be an alcohol (methanol or ethanol) or a non-protic
substance such as ethyl acetate, dioxane or dimethyl-
formamide. Hydrogen pressures of 1-5 atmospheres are
~ 2~ S
_50_ 16068Y
1 employed at temperatures from 25-50C. The reaction is
continued until the theoretical uptake of hydrogen is
observed.
Another process for the preparation of com-
pound IA involves the hydrogenation of precursors havingacetylenic or olefinic bonds in the carbon chain joining
the thiazolidinone and benzene rings.
The acetylenic and olefinic precursors both are
hydrogenated in the presence of palladium as a catalyst.
The palladium advantageously is combined with charcoal as
a supporting substance. A solvent is employed which may
be an alcohol ~methanol or ethanol) or a non-protic sub-
stance such as ethyl acetate or dioxane. Hydrogen pres-
sures of 1 to 5 atmospheres are employed at temperatures
of 20-40C. The reactions are continued until the theore-
tical amounts of hydrogen are absorbed (2 molar equival-
ents for acetylenes, 1 molar equivalent for olefins).
In another method, a compound of the formula
IIA in which X is halogen (chlorine, bromine, or iodine)
is treated with an alkali or alkaline earth metal or metal
compound, preferably magnesium or butyllithium, to pro-
duce a compound of the formula IIIA:
~ ~ M
IIA IIIA
(M is alkali or alkaline
earth metal)
Compound IIIA is treated with carbon dioxide
followed by acid workup to product compound IA. Best
24~S
-51- 16068Y
l yields are obtained when the metallation is done at low
temperature and reaction with carbon dioxide is performed
promptly, not allowing the metallated intermediates to
stand. Inert aprotic organic solvents are required.
Ethers such as diethyl ether, tetrahydrofuran, or dioxane,
are preferred.
Another such process includes treatment of a
thiazolidinone compound having a 2-(3-halopropyl) sub-
stituent with a 4-metallobenzoic acid salt such as the
organocopper reagent shown in the following formulation:
~S ~ I Cu ~ COOCu
IA
The reaction may be carried out in ether or
tetrahydrofuran at -20 to 25C. for a period of 3 to 5
hours. Acidic workup produces IA.
The following processes are methods for the
formation or placement of the hydroxycyclohexylethyl side
chain in the 3-position of the thiazolidinone ring.
One such process involves alkylation of an
imino ether of the formula:
~ ~ CO2Li
RO
with a hydroxycycl~hexylethyl halide. Methyl and ethyl
iminoethers are preferably used in the alkylation. An
iodide is always preferred to a bromide as an alkylation
~g.z~2~xS
-52- 16068Y
1 reagent. The reaction may be carried out in dimethyl-
formamide (DM~), hexamethylphosphoric triamide (HMPA), or
tetrahydrofuran (~HF). The recommended reaction tempera-
ture range is 25-100C. and reaction times range from 5
to 24 hours.
~ nother such process involves preparation of
compound IA via alkylation of a thiazolidinone with an
iodide. Lithium hydride, sodium hydride, and potassium
hydride can be used to generate the thiazolidinone anion.
The alkylation can be carried out in DMF, HMPA, TH~, DME,
and other polar non-protic solvents. The reaction tem-
perature is preferrably in the range of 0 to 70C. and
the duration of the reaction is 2 to 24 hours.
Another such process involves the preparation
of compound IA by reaction of a metallo derivative of a
1,5-dihalopentane with a substituted thiazolidinone of
the formula:
~COO~
in which R is carboxy or derivative, as for example,
carboxy ester or carboxylic acid halide. In this pro-
cess, a metallo derivative is treated at low temperature,from -7~C. to reflux temperature, preferably -40 to
0C. for very active metals and 0C. to reflux for less
active metals~ Solvents for the reaction are inert apro-
tic solvents such as diethyl ether, tetrahydrofuran, or
dioxane.
Another related process utilizing similar re-
action conditions involves the intramolecular cyclization
of a substituted thiazolidinone of the formula:
~.Z4Z~S
-53- 16068Y
/~ ~/ ~ ~ COOH
X
1 wherein X is halo (bromo, chloro, or iodo) by reaction of
said compound with an alkaline earth metal, preferably
magnesium, followed by hydrolysis.
Another such process using organometallic inter-
mediates involves similar reaction conditions and involves
reacting a N-haloethyl compound of the formula:
<S ~ COOH
~ ~ Halogen
o
under Grignard conditions with cyclohexanone followed by
hydrolysis. A bromo or halo thiazolidinone is treated
with a metallation agent, such as magnesium or lithium, in
a polar aprotic solvent, such as ether or tetrahydrofuran,
at 0C. to reflux temperatures for 1-24 hours, under an
atmosphere of argon or nitrogen. The resulting metallated
species are treated with one e~uivalent of cyclohexanone
to form the desired thiazolidinone IA.
Alternatively, the next lower homolog of the
preceding N-haloethyl compound is treated after metala-
tion, with methylenecyclohexane oxide in an aprotic sol-
vent, preferably ether or tetrahydrofuran, at 4C. to
reflux temperatures for 1 to 24 hours, to give compound
IA after acidic workup.
Another process involves the preparation of
compound IA by hydration of an olefinic precursor. Such
an olefin is preferably A, but may be B:
.,
, . . -
~ z4~r~5
~54~ 16068Y
~C02~ ~}C02~
1 Hydration is accomplished by use of a variety
of reagents, each of which adds to the double bond to
form an intermediate, often of low stability, which is
not isolated but is converted to the desired hydroxy com-
pound in a work-up procedure. Two broad classes of hydra-
tion procedures are particularly advantageous:
(1) Addition of an acid to the double bond to qive
an intermediate, non-isolated ester which is hydrolyzed
on workup to the hydroxy compound. Especially useful
acids are trifluoroacetic acid and sulfuric acid or for-
mic acid with a catalytic amount of sulfuric acid or
acetic acid with a catalytic amount of sulfuric acid.
The process is depicted in the following general formulas:
<S ~ CO2H H-O-Z >
~ N ~ (Z = acyl or S02-OH)
~J
_
Ln } C2~ ~ IA
on-isolated intermediat
The addition of acid is conducted in an excess
of acid as a solvent at temperatures of 20-40C. for 2-8
hours.
-55- 16068Y
1 (2) The oxymercuration-demercuration process: Here
a mercuric salt, preferably mercuric acetate or mercuric
trifluoroacetate adds to the olefinic bond to give a non-
isolated mercury compound. This reaction is conducted in
aqueous tetrahydrofuran at 10-40C. for 20-48 hours. The
mercury addition compound is not isolated but is treated
in solution with sodium or potassium borohydride in sodium
hydroxide solution to reduce mercury II to metallic mer-
cury and provide the desired hydroxy compound. Reaction
with the borohydride reagent is instantaneous and is con-
ducted at 0-25C. The generalized formulation is:
S ~ CO2H Hg(OAc)2
THF
O I~J H20
S ~ C2H- NaBH4 IA
S_N~HgOAc >
the presumed, non-isolated
intermediate
Another suoh process for the elaboration of the
N-substituent side chain includes processes for removal
of a hydroxy protecting group thereby regenerating the
hydroxyl substituent with production of compound IA. The
protecting group replacing the hydrogen of the hydroxyl
is tetrahydropyranyl, alkyl, alkanoyl, aroyl, trialkyl-
silyl, alkoxyalkyl, alkylthioalkyl, benzyl, alkoxycarbonyl,
and is represented by X in formula VI:
~ Z~2~5
56- 16068Y
~S ~ C~OH
~ N ~ VI
1 In one such process, when X equals trialkyl
silyl, vinyl ether, vinyl thioether, tetrahydropyranyl,
thioacetal, thioketal, tetrahydrofuranyl, acetal, ketal,
monothioacetal, monothioketal, acyl, aroyl, trityl, or an
analogous group, then deprotection occurs by treatment
of the above thiazolidinone Vl with a Lewis acid, such as
~g , Ag , Zn , or Mg , or a mineral acid, as HCl,,
H2SO4, or an organic acid, as p-toluene sulfonic acid,
in a polar protic solvent, as water or ethanol, at room
temperature for 1 to 24 hours.
In another process for preparing the desired
product, the protective substituent containing an a-halo
substituent ~e.g., a 3-bromo-tetrahydro-2-pyranyl group)
is removed by treatment in a polar-protic solvent, pre-
ferably methanol, ethanol, or acidic acid, with a metalsuch as zinc at temperatures from 25C. to the reflux
temperature of the solvent from 1 to 24 hours.
In a further process involving alkylative hydro-
lysis to product compound IA. a derivative in which the
hydroxyl substituent is protected as an alkyl monothio-
acetal or an alkyl monothioketal is treated with an
alkylating agent, such as methyl iodide or dimethyl sul-
fate, at 0-50C. in a polar solvent, such as ether or
tetrahydrofuran, to form the alkylated compound which is
then hydrolyzed by direct treatment with water at 0-50C.
or 1 to 24 hours.
: :-.-::
-57- 16068Y
1 In an alternate process where the hydroxyl pro-
tective substituent of compound IA is alkanoyl of 1 to 5
carbon atoms, aroyl, alkoxycarbonyl, or carbamoyl, the
protective group is removed and the desired compound
produced by alkaline hydrolysis or saponification. The
protected compound is treated with a base, such as sodium
bicarbonate, sodium hydroxide, or potassium hydroxide,
in an aqueous or preferably aqueous methanol, aqueous
tetrahydrofuran, or comparable solvent system, at 25C.
to reflux temperatures from 1 to 24 hours.
In an alternate process for elaborating the
hydroxycyclohexylethyl substituent, the ether derivative
of the hydroxy substituent, i.e., a lower alkyl ether or
a benzyl ether, is treated with a nucleophile or latent
nucleophile, such as lithium diphenyl phosphine, trimeth-
ylsilyl iodide, or iodine/diborane, in a polar solvent,
at temperatures from 0C. to reflux for 1-24 hours.
In a further alternate method, the benzyl ether
of IA (i.e., compound VI where X = benzyl) is treated
with hydrogen over a suitable catalyst, such as palladium
on carbon or platinum, in a inert solvent such as meth-
anol, ethanol, or acetic acid, at temperatures from 0-
50C. for 1-24 hours.
In another method, trialkylsilyl or triaryl-
silyl ethers of compound IA are converted to IA by treat-
ment with a silylophile such as fluoride ion in a polar
aprotic medium, preferably tetrahydrofuran, at 0-50C.
for 1-24 hours.
In another alternate process in which the hy-
droxy hydrogen of compound IA is replaced by a photo-
lytically labile group as for example an o-nitrobenzyl
group, the desired compound IA can be regenerated by
~.z~24t5
-58- 1606~Y
1 radiation with light. In this process, a solution of
the photolabile compound is radiated at 200-400 nm. in a
polar solvent such as methylene chloride at 0-40C. for
1-24 hours, resulting in complete deprotection of the
alcohol function.
In a still further process for removal of the
hydroxy protecting group, the compound VI having a 2,2,2-
trichloroalkoxycarbonyl substituent is subjected to elec-
trolysis. A solution of the compound in a conducting
solvent such as water or an alcohol-water mixture is
charged with a current of 0.1 to 5.0 volts at 0-25C.
for 1-24 hours.
In an alternate process for the elaboration of
the hydroxycyclohexylethyl side chain, a precursor which
has the hydroxyl hydrogen replaced by a labile substitu-
ent of the formula:
O
is converted to compound I~ by enzymatic hydrolysis. A
solution of the protected alcohol in an a~ueous buffer
system, preferably potassium phosphate, is treated at
20-37C. for 1 to 24 hours with a hydrolytic enzyme such
as chymotrypsin.
In another process for producing the product by
elaboration of the hydroxycyclohexylethyl side chain, an
ester of the hydroxy group is removed by ammonolysis.
The ester is either lower alkanoyl, aroyl, or in a pre-
ferred instance, r-keto alkanoyl. To produce the desired
compound, an ester of compound IA is dissolved in a polar
Z~5
-5~ 16068Y
1 solvent preferably tetrahydrofuran and treated with an
amine, such as ammonia or hydrazine, at 0C. to reflux
temperature, from 1 to 24 hours.
In another group of processes, compound IA is
S produced by a reaction that forms the thiazolidinone ring
system.
In one such for producing the desired compound
by elaboration of the thiazolidinone ring, a suitably
substituted imine is treated with mercaptoacetic acid or
an ester thereof under azeotropic conditions. The sol-
vents employed are preferably aprotic, water immiscible
solvents such as benzene, toluene, or xylenes. The re-
action is carried out at the boiling temperature of the
solvent for a period of 5-24 hours.
A further process describes the preparation of
the desired compound by the condensation of a N-alkyl-
mercaptoacetamide and an aldehyde under azeotropic con-
ditions. Benzene, toluene, or xylenes may be used as
solvents. The reaction is carried out at the boiling
temperature of the solvent for the duration of 5~-24
hours. Preferably aryl and alkylsulfonic acids (e.g.,
p-toluenesulfonic acid, methanesulfonic acid) are used
to catalyze the condensation.
In another process for assembly of the thia-
zolidinone ring, a direct condensation of 4-(4-oxobutyl)-
benzoic acid, 1-(2-aminoethyl)cyclohexanol and mercapto-
acetic acid is carried out under azeotropic conditions.
Benzene, toluene, or xylenes may be used as solvents.
The reaction is carried out at the boiling temperature of
the solvent for a period of 7 to 24 hours.
A still further method of elaboxation of the
thiazolidinone ring involves the reduction (deoxygenation)
of a sulfoxide precursor. A variety of agents can be
-60- 16068Y
1 used to effect reduction (e.g., triphenylphosphine in
acetic acid), but the preferred process involves a cata-
lytic hydrogenolysis. The catalyst is palladium which
may be combined with charcoal as a supporting substance.
Hydrogen pressures of 60 to 100 atmospheres are employed
at temperatures ranging from 70-100C. The reaction is
continued until the theoretical amount of hydrogen is
absorbed. A solvent is employed which may be ethanol or
dioxane.
A further process for the elaboration of the
thiazolidinone ring of IA is the hydrolysis of the 4-halo-
thiazoline compound having the formula:
~ ~ COOH
X HOV
wherein X is halogen including bromine, chlorine, or
iodine. The 4-halothiazoline is treated in aqueous media
with a strong acid, preferably hydrochloric or sulfuric
acid, for a period of 1-2 hours at a temperature of 0-
40C.
~.2~5
- 61 - 1606~Y
1 EXAMPLE 37
Preparation of I from N,N-Dimethyl-4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl~-4-oxo-2-thiazolidinyl]propyl}benzamide
bY HYdrolYS i s
. _ ~ . _ . _ . . _ . . . _ . _
Step A: Preparation of N,N-Dimethyl-4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-
~ro~Yl~benzamide
A solution of ethyl 4-{3-[3-[2-(1-hydroxycyclo-
hexyl)ethyl] 4-oxo-2-thiazolidinyl]propyl~benzoate (4.2
g.; 0.01 mole) and dimethylamine (4.5 g., 0.1 mole) in
ethanol (40 ml.) is placed into a pressure bottle. The
bottle is sealed and heated at 60-65~C. for 48 hours.
The bottle is cooled, opened, and the solution e~aporated
at reduced pressure to leave the crude dimethylamide pro-
duct as a very viscous residual oil.
Step B: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A solution of the dimethylamide of Step A (0.01
mole) and sodium hydroxide (1.6 g., 0.04 mole) in meth-
anol (40 ml.) and water (10 ml.) is heated at 60C. for
48 hours. The solution is then diluted with water (50
ml.) and extracted with methylene chloride. The aqueous
layer is acidified with 6N hydrochloric acid to precipi-
tate the title product.
:EXAMPLE 38
Hydrolysis of 4- ~ 3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzonitrile
Step A: Preparation of 4-~3-[2-(1,3-Dioxolanyl)]propyl~-
benzonitrile
_,.
n-Butyl lithium solution (2.2 M in hexane, 2.62
ml., 58 mmol.) is added to a stirred solution of diiso-
- ~ za~z~5
-62- 16068Y
1 prop~lamine (8.83 ml., 63 mmol.) in anhydrous tetrahydro-
furan (THF, 150 ml.) and hexamethylphosphoramide (HMPA,
13.8 ml~) at 0C. under a nitrogen atmosphere. After 10
minutes, a solution of p-tolunitrile (6.15 g.~ 53 mmol.)
in 20 ml. of THF is added to give a dark, red-brown re-
action mixture. The deep-colored solution is stirred one
hour at 0C. and then is treated with a 20 ml. of THF
containing 2-(2-bromoethyl)-1,3-dioxolane. After one
hour, the dark green reaction mixture is quenched with
cold water and extracted with diethyl ether. The com-
bined organic extracts are washed with lN HCl solution
and brine, then dried over anhydrous magnesium sulfate
and concentrated to give an oily residue. Distillation
of the residue at 132-137C./15 mm. Hg. affords 6.2 g.,
of the title compound.
Anal- Calc'd for C13H15N2 C, 71-86; H, 6-96; N~ 6-45
Found: C, 71.71; H, 7.10; N, 6.31
Step A-2: Preparation of 4-Oxobutylbenzonitrile
4-~3-[2-(1,3-dioxolanyl)]propyl~benzonitrile
(4.5 g., 20.7 mmol) is dissolved in 45 ml. of water and
90 ml. of acetic acid containing 1 ml. of concentrated
hydrochloric acid. The resulting solution is heated at
60C. for 2 hours, cooled to room temperature, and care-
fully neutralized with sodium bicarbonate solution. The
aqueous reaction mixture is extracted with ether. The
combined extracts are dried over anhydrous potassium
carbonate and concentrated to give the 3.4 g. of the
title compound as an oil.
Step B: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl~propyl~enzonitrile
The product (3.7 g., 21.3 mmol.) obtained above
in Step A-2 is treated at room temperature with 2 ml. of
f~
-63- 16068Y
1 carbon tetrachloride containing 1-amino-2-[(1-hydroxy)-
cyclohexyl]ethane (3.21 g., 22.4 mmol.). Sodium sulfate
(4 g.) is added and the whole is stirred for 2 hours.
The reaction mixture is filtered and the filtrate is
diluted with 70 ml. of benzene and treated with 2.06 g.
(22.4 mmol.) of thioglycolic acid. The resulting reac-
tion mixture is refluxed several hours, cooled and washed
in succession with 5% HCl solution, saturated sodium bi-
carbonate solution, and brine. The organic phase is
dried over anhydrous magnesium sulfate and concentrated
: to give an oil which is purified by chromatography on
silica gel using 2% methanol in chloroform to give 2.8 g.
of the analytically pure specimen.
Anal. ~alc'd for C21H27N2O2S: ,
15 Found: C, 67.3; H, 7.82; N, 7.1
Step C: Preparation of IA by Hydrolysis of 4-~3-[3-[2-
(l-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidin-
yl]prop~l~benzonitrile
To a cold solution of sodium hydroxide t4.8 g.,
20 120 mmol.) in 50 ml. of water is àdded 3.7 g. (100 mmol.)
of 4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thia-
zolidinyl]propyl~benzonitrile. The mixture is allowed
to stand overnight below 30C. The reaction mixture is
then slowly warmed to 90C. over a 2 hour period and main-
tained at that temperature for 3 hours more. The reaction
mixture is then cooled to room temperature and carefully
rendered acidic with 6N sulfuric acid. Chloroform is
added and the phases separated. Further extraction of
the aqueous layer with chloroform, followed by drying of
the combined organic extracts over anhydrous magnesium
sulfate and concentra~ion under reduced pressure a~fords
the title compound as an oil which crystallizes on stand-
ing .
Z~S
-64- 16068Y
1 EXAMPhE 39
Preparation of I by Hydrolysis of Ethyl 4-~3-[3-[2-(1-
hydroxycyclohexy~)ethyl]-4-oxo-2-thiazolidinyl]propyl~-
benzimidate Hydrochloride
Step A: Preparation of Ethyl 4-~3-[3-[2-(l-hydroxycyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benz-
imidate Hydrochloride
A ~ixture of benzene (20 ml.) and ethanol (5
ml.) is saturated with hydrogen chloride at 0C. 4-~3-
[3-[2~ Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-
propyl~benzonitrile (3.7 g., 0.01 mole) is added and the
resulting solution is stored at -5 to 0C. for 24 hours.
Addition of ether (50 ml.) precipitates the title imidate
hydrochloride product.
Step B: Preparation of 4-~3-[3-[2-(l-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
The imidate hydrochloride of Step A (0.01 mole)
is added to a solution of sodium hydroxide ~0.6 g., 0.04
mole) in water (lO ml.) and methanol (40 ml.). The re-
sulting solution is heated at 60-65C. for 48 hours. The
solution is ~ooled, diluted with water (50 ml.), and ex-
tracted with chloroform. The aqueous solution is acidi-
fied with 6N hydrochloric acid to precipitate the title
product as an oil which crystallizes.
ExAMæLE 40
Preparation of ~ by Hydrolysis of Ethyl 4-~3-[3-[2-(l-
hydroxycyclohexy~)ethyl]-4-oxo-2-thiazolidinyl]propyl~-
benzthioimidate Hydrochloride
Step A: Preparation of Ethyl 4-~3-[3-[2-(l-hydroxycyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benz-
thioimidate Hydrochloride
A mixture of benzene (20 ml.) and ethanethiol
(3 ~lo) is saturated with hydrogen chloride at 0C.
~ 2~Z~S
-65- 16068Y
l 4-~3-[3-[2-(l-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl}benzonitrile (3.7 g., O.Ol mole) is added
and the resulting solution is stored at -5 to 0C. for
24 hours. Addition of ether (50 ml.) precipitates the
title thioimidate hydrochloride product.
Step B: Preparation of 4-~3-[3-[2-(l-Hydroxycyclohexyl)-
ethvl]-4-oxo-2-thiazolidinYl]PropYl~benzoic Acid
The thioimidate hydrochloride of Step A (O.Ol
mole) is added to a solution of sodium hydroxide (l.6 g.,
0.04 mole) in water (lO ml.) and methanol (40 ml.). The
resulting solution is heated at 60-65C. for 48 hours.
The solution is cooled, diluted with water (50 ml.) and
extracted with chloroform. The aqueous solution is acid-
ified with 6N hydrochloric acid to precipitate the title
product as an oil which crystallizes.
EXAMPLE 41
Preparation of Compound I by Hydrolysis of 2-~4-[3-[3-
[2-(l-Hydroxycyclohexyl)e ~ yl]-4-oxo-2-thiazolidinyl]-
propyl~phenyl~-4,4-dimethyl-2-oxazoline
Step A: Preparation of 2-~4-~3-12-(1,3-Dioxolanyl)prop-
yl]phenyl]~-4 ! 4-dimethyl-2-oxazoline
4-~3-~2-(l,3-Dioxolanyl)]propyl}benzoic acid
(0.25 mol.) is added to 90 g. (0.75 mol.) of thionyl
chloride and the mixture is stirred at 25C. for 24 hours.
The excess thionyl chloride is distilled and the remaining
dark oil is dissolved in lO0 ml. of methylene chloride.
This solution is added in a dropwise manner to a magnet-
ically stirred solution of 39.2 g. (0.44 mol.) of 2-amino-
2-methyl-l-propanol in lO0 ml. of methylene chloride at
0C. The resulting reaction mixture is stirred at 0C.
2~5
-66- 16068Y
1 for 2 hours. The precipitate is filtered, washed with
water, and dried. More solid can be obtained by con-
centrating, cooling, and filtering the methylene chloride
solution. The combined solids (0.25 mol.) are dried and
treated dropwise with stirring with thionyl chloride (35.8
g., 0.30 mol.). When the vigorous reaction has subsided,
the solution is poured into 200 ml. of ether and the re-
sulting solid is filtered. Neutralization of the hydro-
chloride salt with 20% sodium hydroxide solution and
extraction with ether affords the title compound.
Step B: Preparation of 2-[4-(4-Oxobutyl)phenyl]-4,4-
dimethyl-2-oxazoline
This compound is prepared essentially by the
method described in Example 1, Step A-2, except that
: 15 2-~3-[3-[2-~1,3-dioxolanyl)propyl]-phenyl]~-4,4-dimethyl-
2-oxazoline is substituted for ethyl 4-~3-[2-(1,3-dioxol-
anyl)]propyl}benzoate. The title compound is obtained
as a very viscous oil.
Step C: Preparation of 2-~4-[3-[3-[2-(1-Hydroxycyclohex-
yl)ethyl]-4-oxo-2-thiazolidinyl]propyl]phenyl~-
4_,4-dimethyl-2-oxazoline
The synthesis of this compound is carried out
by the procedure of Example 47, Step B, except that t-
butyl 4-(4-oxobutyl)benzoate is replaced by an equivalent
25 quantity of 2-[4-(4-oxobutyl)phenyl]-4,4-dimethyl-2-oxa-
zoline. The title compound is obtained as a viscous
oil.
Step D: Hydrolysis of 2-~4-[3-[3-[2-(1-Hydroxycyclohex-
yl)ethyl]-4-oxo-2-thiazolidinyl]propyl]phenyl~-
4,4-dimethyl-2-oxazoline to Produce Com~ound IA
-
The product (3 mmol.) obtained directly above
in Step C is heated to reflux in 40 ml. of ethanol
~J.'~42~5
-67- 16068Y
1 containing 3.6 ml. of concentrated sulfuric acid under a
nitrogen atmosphere. The reaction mixture is concentra-
ted under reduced pressure to 1/4 volume and then poured
into a saturated salt solution. The aqueous reaction
mixture is extracted with ether. The ether extracts are
washed with 10% sodium bicarbonate solution, dried over
potassium bicarbonate, and concentrated. The title com-
pound is obtained as a semi-solid which crystallizes
further on standing.
EXAMPLE 42
Preparation of Compound IA
S~r~2C2~5 S~COSeCE~3
O HO O ~ ~3 IA
Step A: Preparation of Se-Methyl seleno-4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-
propyl3benzoate
To a 50 ml. side-arm flask containing 4.1 g.
(0.052 mol.) of selenium powder is added 25~2 ml. (0.05
mol.) of a 17% solution of trimethylaluminum in toluene.
The reaction mixture is heated at reflux for 2 hours,
then cooled to room temperature, allowing the unreacted
selenium to settle from solution. A 1.1 ml. (2.2 mmol.)
aliquot of the reaction mixture is transferred by syringe
to a solution of ethyl 4-~3-[3-[2-(1-hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate (2.0 mmol.)
in 5 ml. of argon degassed methylene chloride at 0C.
After 30 minutes at this temperature, the solution is
warmed to room temperature over 30 minutes and then
l~.Z~Z~5
-68- 16068Y
1 treated with moist sodium sulfate. The resulting mix-
ture is extracted with methylene chloride and the title
compound is obtained after evaporation of the combined
dried (magnesium sulfate) extracts.
Step B: Preparation of Compound I by Hydrolysis of Se-
Methyl seleno-4-~3-[3-[2-~1-hydroxycyclohexyl)-
ethyl]-4-oxo-thiazolidinyl]propyl~benzoate
A mixture of Se-methylseleno-4-~3-~3-[2-(1-
hydroxycyclohexyl)ethyl]-4-oxo-thiazolidinyl]propyl~-
benzoate (0.525 mmol.), 293 mg. (1.07 mmol.) of freshly
sublimed mercuric chloride, and 2.4 mg. (2.14 mmol.) of
calcium carbonate in wet acetonitrile (6.0 ml.) is
stirred for 1 hour at room temperature. The reaction
mixture is then diluted with water (30 ml.) and extracted
with chloroform. The organic extracts are filteredthrough Celite, dried ~magnesium sulfate), and evaporated
to give the title compound as a solid.
EXAMPLE 43
Preparation of Compound I from Ethyl 4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-~-oxo-2-thiazolidinyl]propyl~-
benzoate by Hydrolysis under Acidic Conditions
A mixture of ethyl 4-~3-~3-[2-(1-hydroxycyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate (10
mmol.), ethanol (80 ml.), and lN hydrochloric acid (30
ml.) is heated at reflux for 10 hours. The reaction mix-
ture is cooled to room temperature, diluted with water
(200 ml.) and extracted with chloroform. The organic
extract is washed twice with brine, dried over anhydrous
magnesium sulfate, and filtered. Evaporation of the
filtrate in vacuo gives an oil residue which is purified
by column chromatography on silica gel to provide the
title compound.
fh~5
-69- 1~068Y
1 EXAMPLE 44
Preparation of Compound I from Benzyl 4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-~-oxo-2-thiazolidinyl)propyl~-
benzoate by Hydrogenolysis _ __
Step A: Preparation of Benzyl 4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-th_azolidinyl]propyl~-
benzoate
Metallic sodium (0.3 g., 0.013 mole) is added
to benzyl alcohol (6.5 g., 0.06 mole) and the mixture is
stirred and heated at 60C. to effect solution. Ethyl
4-~3-[3-~2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl}benzoate (4.2 g., 0.01 mole) is added and
the resulting solution is heated at 95C. for 8 hours.
The solution i5 cooled and treated with ether (50 ml.)
and water (50 ml.). The ether layer is separated, washed
with three portions of water, and dried over sodium sul-
fate. Evaporation of the solvent leaves the crude benzyl
ester which is purified by chromatography on silica gel
with elution by 2% methanol in chloroform.
Step B: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A solution of the benzyl ester of Step A (0.01
mole) in ethyl acetate (50 ml.) is hydrogenated over 1.5
g. of a 5% palladium on charcoal catalyst at 1 atmosphere
of pressure and 25-27C. until the theoretical amount
(0.01 mole) of hydrogen has been absorbed. The catalyst
is removed by filtration, and the solvent evaporated.
The crude product thus obtained is purified by chroma-
tography on silica gel with 2% methanol in chloroform
elution. The title compound is thus obtained as a cry-
stalline solid.
-70- 16068Y
1 EXAMPLE_45
Preparation of I by Cleavage of Cinnamyl 4-~3-[3-[2-(1-
hydroxycyclohexy~)ethyl]-4-oxo-2-thiazolidinyl]propyl}-
benzoate Using Mercuration-Demercuratlon
Step A: Preparation of Cinnamyl 4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~-
benzoate
Metallic sodium (0.3 g., 0.0013 mole) is added
to cinnamyl alcGhol (8.1 g., 0.06 mole) and the mixture
is stirred and heated at 60C. to effect solution. Ethyl
4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl~benzoate (4.2 g., 0.01 mole) is added and
the resulting solution is heated at 95~C. for 8 hours.
The solution is cooled and treated with ether (50 ml.)
and water (50 ml.). The ether layer is separated, washed
with three portions of water, and dried over sodium sul-
fate. Evaporation of the solvent leaves the crude
cinnamyl ester which is purified by chromatography on
silica gel with elution by 2% methanol in chloroform.
0 Step B: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A mixture of the cinnamyl ester of Step A (0.01
mole), mercuric acetate (0.012 mole), nitric acid (0.001
mole), and methanol (50 ml.) is stirred at 27C. for 4
hours. Solid sodium bicarbonate is added and the mix-
ture stirred at 27C. for 30 minutes. Methanol is then
evaporated at reduced pressure. The residue is stirred
with cyclohexane (50 ml.) and a solution of potassium
thiocyanate (0.10 mole) in water (120 ml.~ for 18 hours
at 27C. The aqueous layer is then separated and acidi-
fied with 6N hydrochloric acid. The title product pre-
cipitates as a viscous oil. It is purified by column
chromatography on silica gel and is thus obtained as a
crystalline solid.
~'2~ 5
-71- 16068Y
1 EXAMPLE 46
Preparation of Compound I by Nonhydrolytic Ester Cleavage
of Ethyl 4-~3-[3-[2-~1-hy~roxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~benzoate
To a solution of ethyl 4-~3-[3-[2-tl-hydroxy-
cyclohexyl)e~hyl]-4-oxo-2-thiazolidinyl]propyl benzoate
(1.25 g., 3 mmol.) in 25 ml. of chloroform is added 8-10
equivalents of freshly distilled trimethylsilyliodide.
The resulting solution is warmed to 50C. for 35 hours,
cooled and poured into 50 ml. of water. The phases are
separated and the aqueous layer is extracted with chloro-
form. The combined organic extracts are dried ovex an-
hydrous potassium carbonate, filtered, and concentrated
to give the title compound.
EXAMPLE 47
Preparation of Compound I by Pyrolysis of t-Butyl-4-~3-
[3-[2-,(1-hydroxycyclohexy~)ethyl]-4-oxo-2-thiazolidinyl]-
propylgbenzoate
Step A: Preparation of t-Butyl-4-(4-Oxobutyl)benzoate
Step A-l: Preparation of 4-~3-[2-(1,3-Dioxolanyl)]prop-
yl}benzoic Acid
-
n-Butyl lithium solution (2.3 M in hexane;
17.5 ml., 40 mmol.) is added dropwise at 0C. to a mag-
netically stirred solution of diisopropylamine (4.04 g.,
40 mmol.) in dry tetrahydrofuran (THF) and hexamethyl-
phosphoramic triamide (HMPA, 5 ml.) under nitrogen.
To this solution is added 2.77 g. (20 mmol.) of ~-toluic
acid in 10 ml. of THF to give a green-brown reaction mix-
ture. Stirring is continued for 30 minutes at 0C.
before 2-(2-bromoethyl)-1,3-dioxolane in 5 ml. of THF is
-7~- 16068~
1 added and then for 30 minutes more after addition is com-
plete. The reaction mixture is quenched with cold water
and the organic phase is separated. The aqueous layer
is acidified with hydrochloric acid (2N) and then ex-
S tracted with ether. The combined ethereal extracts aredried over anhydrous magnesium sulfate, filtered and
evaporated to give a solid residu~.
Step_A-2: Preparation of t-Butyl-4-~3-[2-(1,3-dioxolan-
vl)]~ro~vl~benzoate
The solid residue (obtained above in Step A-l)
is suspended in benzene and treated with oxalyl chloride
(3.5 ml., 40 mmol.). This reaction mixture is heated at
45C. for 3 hours. The solvent and excess reagent are
then removed under reduced pressure to give an oil which
is treated at 0C. with t-butanol (2.85 ml., 30 mmol.)
and triethylamine (4.2 ml., 30 mmol.) in 20 ml. of THF
at 5C. The reaction mixture is poured into 50 ml. of
water after one hour and extracted with ether. The com-
bined ethereal extracts are washed with brine, dried over
anhydrous magnesium sulfate, and rotoevaporated to give
the title compound as an oil.
Step A-3: Preparation of t-Butyl-4-(4-oxobutyl)benzoate
-
The product obtained in Step A-2 above is con-
verted to the title compound using identical conditions
to those described in Example 1, Step A-2. The title
compound is isolated as an oil.
Ste~_~: Preparation of t-Butyl-4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyI]-4-oxo-2-thiazolidinyl]propyl}-
benzoate
t-Butyl-4-(4-oxobutyl)benzoate (0.76 le) is
added dropwise during 20 minutes to a stirred solution
~.Z42~5
_73- 16068Y
1 of 1-(2-aminoethyl)cyclohexanol (129.5 g., 0.91 mole) in
toluene (500 ml.). The mi~ture is stirred at 30C. for
30 minutes and then refluxed using a Dean-Stark water
separator for 30 minutes until all the water is removed.
Toluene (500 ml.), methyl thioglycollate (118.7 g., 1.12
mole) and triethylamin~ (30 ml.) are then added. The
solution is boiled under reflux for 21 hours. It is
then cooled, washed with 2N hydrochloric acid and water
and dried over sodium sulfate. Evaporation of the sol-
vent gives the title product as a viscous oil.
Step C: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-
benzoic Acid
A solution of the product (1.12 g., 2.5 mmol.)
obtained above in Step B is boiled under reflux for 22
hours in toluene (60 ml.) in the presence of p-toluene-
sulfonic acid (47 mg., 0.25 mmol.). The solution is
cooled, washed with saturated sodium bicarbonate solution
and brine, and dried over anhydrous sodium sulfate. The
solvent is distilled leaving a viscous residual oil com-
prising compound IA, which crystallizes immediately on
standing.
EXAMPLE 48
_
Preparation of Compound I from Trimethylsilylethyl-4-
~3-[3-[2-(1-hydroxycycloh~xyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl}benzoatè
Step A: Preparation of Trimethylsilylethyl 4-(4-oxobut-
yl)benzoate
Step A-l: Preparation of 4-~3-[2-(1,3-Dioxolanyl)]prop-
yl~benzoic Acid
The preparation of this compound is carried
~ ~4Z~-~S
-74- 16068Y
1 out using the same procedure described in Example 47,
Step A-l.
Step A-2: Preparation of Trimethylsilylethyl 4-~3-[2-
(1,3-dioxolanyl)]propyl}benæoate_
The product (2.36 g., 10 mmol.) obtained in
Step A-l above is dissolved in 10 ml. of acetonitrile and
treated at ice bath temperature with 1.6 ml. of pyridine
and 1.7 ml. of 2-trimethylsilylethanol. After 10 minutes
dicyclohexylcarbodiimide (2.25 g., 11 mmol.) is added
and stirring is continued at 0C. for an additional 7
hours. The reaction mixture is then treated with 0.3 ml.
of 5M oxalic acid solution in dimethylformamide (DMF) and
the resulting precipitate is removed by filtration after
0.5 hour and washed with ethyl acetate. The filtrate and
organic washings are combined and washed with lN HCl
solution and 10~ sodium bicarbonate solution. The organ-
ic phase is then dried over anhydrous potassium carbonate,
filtered, and concentrated to an oil which is purified by
silica gel chromatography (hexane-ethyl acetate) to give
the title compound in analytical form.
Step A-3: Preparation of Trimethylsilylethyl-4-(4-oxo-
butyl)benzoate
This compound is prepared essentially by the
method described in Example 1, Step A-2, except that
trimethylsilylethyl 4-~3-[2-(1,3-dioxolanyl)]propyl}benz-
oate is substituted for ethyl 4-~3-[2-(1,3-dioxolanyl)]-
propyl~benzoate. The title compound is obtained as a
residual oil.
Step B: Preparation of Trimethylsilylethyl-4-~3-[3-[2-
(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl~benzoate
~he synthesis of this compound is carried out
by the procedure of Example 47, Step B, except that
"
Z4~5
-75- 16068Y
1 t-butyl 4-(4-oxobutyl)benzoate is replaced by an equival-
ent ~uantity of trimethylsilylethyl 4-(4-oxobutyl)benz-
oate. The title compound is obtained after silica gel
chromatography as an oil.
Step C: Preparation of Compound IA
The reaction product (0.53 g., 1.07 mmolO)
obtained above in Step B is dissolved in 9 ml. of dry
dimethylformamide and treated at 29C. with a solution
of tetra-n-butylammonium fluoride in dimethylsulfoxide
(1.25 ml., 2.1 M, 2.6 mmol.). Gas evolution commences
immediately. After 10 minutes, 10 ml. of water is care-
fully added with cooling and the reaction mixture is
concentrated under reduced pressure to approximately 4
ml. The residual liquid is diluted with ethylacetate
and rendered acidic with 2N HCl solution. The organic
phase is washed with water, dried over anhydrous mag-
nesium sulfate, and concentrated to give the title com-
pound as an oil which crystallizes.
ExAMæLE 49
Preparation of Compound IA by Reductive Elimination of
~ Trichloroethyl-4-~3-[2-(1-hydroxycyclohexyl)ethyl]-
4-oxo-2-thiazolidinyl]pr ~ zoate
Step A: Preparation of ~ Trichloroethyl-4-~3-[2-
~1,3-dioxolanyl)]propyl~benzoate
4-~3-~2-(1,3-Dioxolanyl)]propyl~benzoic acid
(2 mmol.) is added to a solution of 100 ml. of toluene
containing ~ -trichloroethanol (10 mmol.) and p-tolu-
enesulfonic acid (0.1 mmol.). The resulting reaction
mixture is refluxed with continuous removal of water via
a Dean-Stark trap. After water formation has ceased, the
Z~5
-76- 16068Y
1 solution is cooled to room temperature and partitioned
between ether and sodium bicarbonate solution (10%). The
organic extracts are combined, washed with brine, dried
over anhydrous magnesium sulfate, and evaporated to leave
a residual oil.
Step B: Preparation of ~ -Trichloroethyl-4-(4-oxo-
butyl)benzoate
. . ... ~
This compound is prepared essentially by the
method described in Example 1, Step A-2, except that
~ -trichloroethyl-4-~3-[2-(1,3-dioxolanyl)]propyl~-
benzoate is substituted for ethyl 4-~3-[2-(1,3-dioxol-
anyl)]propyl~benzoate. The title compound is obtained
as a residual oil.
Step C: Preparation of ~ -Trichloroethyl-4-~3-[3-[2-
(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidin-
~l]propyl}benzoate
The synthesis of this compound is carried out
by the procedure of Example 47, Step B, except that t-
butyl 4-(4-oxobutyl)benzoate is replaced by an equivalent
quantity of ~ -trichloroethyl-4-(4-oxobutyl)benzoate.
The title compound is obtained as a viscous oil.
Step D: Preparation of Compound IA by Reductive Elimina-
tion
The product (2 mmol.) obtained in Step C above
is dissolved in methanol and refluxed with vigorous
stirring in the presence of zinc dust (30 mmol.). The
suspension is cooled and filtered through Celite (meth-
anol wash). Evaporation of the filtrate leaves the title
compound as a viscous oil which crystallizes.
~L~3.~ 5
-77- 16068Y
1 EXAMPLE 50
Preparation of Compound IA by Cleavage of Methylthio-
methyl 4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~benzoate
Step A: Preparation of Methylthiomethyl-4-~3-[2-(1,3-
dloxoanyl)]propyl~benzoate
4-~3-[2-(1,3-Dioxolanyl)]propyl~benzoic acid
(2 mmol.) is treated with chloromethyl methyl sulfide
(2 mmol.) and triethylamine (2 mmol.) in acetonitrile
(60 ml.) and the resulting solution is heated to reflux
for 24 hours. The solvent is removed under reduced pres-
sure and the residue washed with dry benzene. Evapora-
tion of the benzene solution affords the title compound
in essentially pure form as a liquid.
Step B: Preparation of Methylthiomethyl-4-(4~oxobutyl)-
benzoate
This compound is prepared by the same method
described in Example 1, Step A-2, except that methyl-
thiomethyl-4-~3-[2-(1,3-dioxolanyl)]propyl~benzoate is
substituted for ethyl 4-~3-[2-(1,3-dioxolanyl)]propyl}-
benzoate. In this way, the title compound is obtained
as a clear, malodorous liquid.
Step C: Preparation of Methylthiomethyl 4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-
propyl~benzoate
The synthesis of this compound is carried out
by the procedure of Example 47, Step B, except that t-
butyl 4-(4-oxobutyl)benzoate is replaced by an equivalent
quantity of methylthiomethyl-4-(4-oxobutyl)benzoate. The
title compound is obtained as a viscous oil.
-78- 16068Y
Step D: Preparation of Compound I from Methylthiomethyl
4-~3-[3-~2-(l-hydroxycycloAhexyl)ethyl]-4-oxo-2
thiazolidinyl]propyl~benzoate
The product (1 mmol.~ obtained in Step C above
is treated at 23C. with trifluoroacetic acid (1 ml.) for
15 minutes. The reaction mixture is diluted with water
(50 ml.) and extracted with chloroform. The combined
organic extracts are washed with brine, dried over anhy-
drous potassium carbonate, and rotoevaporated to give the
compound IA as a viscous oil which crystallizes.
EXAMPLE 51
Preparation of Compound IA by Reductive Cleavage of 2-
Anthra~uinomethyl 4-~3-[3-[2-(1-hydroxycyclohexyl)ethyl]-
4-oxo-2-thiazolidin~]propyl}benzoate
(l~3-dioxolaonyl)]Anthra~uinomethyl-4-~3-[2-
4-~3-[2-(1,3-Dioxolanyl)]propyl~benzoic acid
(3.5 mmol.) is dissolved in 25 ml. of dry dimethyl-
formamide (DMF) and treated in one portion with dicyclo-
hexylcarbodiimide (3.5 mmol.) and hydroxybenzotriazole(3.5 mmol.) under a nitrogen atmosphere. The resulting
reaction mixture is stirred at room temperature for 20
hours and diluted with 200 ml. of ether. The solids are
filtered and the filtrate is washed in succession with
10% sodium bicarbonate solution, water, and brine. The
combined organic phases are dried over anhydrous magne-
sium sulfate and evaporated to give the title substance.
Step B: Preparation of 2-Anthraquinomethyl-4-(4-oxo-
butyl)benzoate _ _
This compound is prepared by the same method
described in Example 1, Step A-2, except that 2-anthra-
quinomethyl-4-~3-[2-(1,3-dioxolanyl)]propyl~benzoate is
s
-79- 1606~Y
1 substituted for ethyl 4-~3-[2-(1,3-dioxolanyl)]propyl~-
benzoate. In this way, the title compound is obtained
as a solid.
Step C: Preparation of 2-Anthraquinomethyl 4-~3-[3-[2-
(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl~benzoate
The synthesis of this compound is carried out
by the procedure of Example 47, Step B, except that t-
butyl 4-(4-oxobutyl)benzoate is replaced by an equivalent
quantity of 2-anthraquinomethyl-4-(4-oxobutyl)benzoate.
The title compound is obtained as a solid.
Step D: Preparation of Compound I by Reductive Cleavage
of 2-Anthraquinomethyl 4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-
benzoate
The product (1.5 mmol.) obtained above in StepC is dissolved in dimethylformamide (DMF, 15 ml.) and
reacted with 9-hydroxyanthrone (6 mmol.) and triethyl-
amine (3 mmol.). The reaction mixture is stirred for 6
hours at 23C. and partitioned between water and chloro-
form. Extraction of the aqueous layer with chloroform
(3 x 30 ml.) is followed by washing the combined organic
extracts with brine. ~he extracts are dried (magnesium
sulfate) and evaporated to dryness to give a solid resi-
due which is recrystallized from acetonitrile to givethe title compound in analytically pure form.
EXAMPLE 52
Preparation of Compound I by Oxidative Cleavage of 4-~3-
[3-[2-(1-Hydroxycyclohexy~)ethyl]-4-oxo-2-thiazolidinyl]-
propyl~benzoic Acid Hydrazide
Step A: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)
ethyl]-4-oxo-2-thiazolidinyl]propyl7benzoic Acid
Hydra z i de
Z~
-80- 16068Y
l Ethyl 4-~3-[3-[2-(l Hydroxycyclohexyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl}benzoate (2 mmol.) is dis-
solved in 25 ml. of absolute ethanol and treated with
hydrazine (64%, 2.1 mmol.) at room temperature. The re-
sulting solution is refluxed for 2 hours, cooled to 23C.
and evaporated to give the title compound as a viscous
oil. The title compound decomposes slowly on exposure
to air and light and is used in the next step without
further purification.
O Step B: Preparation of Compound I by Cleavage of 4-~3-
[3-[2-(l-Hydroxycyclohexy~)ethyl]-4-oxo-2-thia-
zolidinyl]propyl}benzoic Acid ~ydrazide
To a suspension of 4-~3-[3-12-(l-hydroxycyclo-
hexyl)ethyl~-4-oxo-2-thiazolidinyl]propyl}benzoic acid
hydrazide (l mmol.) in 75~ aqueous acetonitrile (8 ml.)
is added, in one portion, powdered ceric ammonium nitrate
(1.65 g., 3 mmol.). After gas evolution ceases, the re-
action mixture is poured into water (lO ml.) and extrac-
ted with chloroform (2 x 30 ml.). The title compound is
obtained by evaporation of the dried (magnesium sulfate)
extract and recrystallization from acetonitrile.
ExAMæLE 53
Preparation of Compound I by Reductive Elimination of
2-~-Toluenesulfonylethyl ~-~3-[3-[2-(l-hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate __ _
Step A: Preparation of 2-p-Toluenesulfonylethyl-4-~3-
[2-(l,3-dioxolanyl)]propyl}benzoate
4-~3-[2-(l,3-Dioxolanyl)]propyl~benzoic acid
(5 mmol.) is treated with 2-p-toluenesulfonylethanol (5
mmol.) and the mixture is refluxed in toluene (lO0 ml.)
for 12 hours in the presence of p-toluenesulfonic acid
~ L~L S
-81- 16068Y
1 (0.5 mmol.). The solution is cooled to room temperature,
washed with sodium bicarbonate solution (10%) and brine,
then dried (magnesium sulfate) and concentrated to afford
the title compound as an oil.
Step B: Preparation of 2-p-Toluenesulfonylethyl-4-(4-
oxobutyl)benzoate
This compound is prepared by the same method
described in Example 1, Step A-2, except that 2-~-tolu-
enesulfonylethyl-4-~3-[2-(1,3-dioxolanyl)]propyl~benzo-
ate is substituted for ethyl 4-~3-[2-(1,3-dioxolanyl)]-
propyl~benzoate. In this way, the title compound is
obtained as an oil.
Step C: Preparation of 2-~-Toluenesulfonylethyl 4-~3-
[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thia-
zolidinyl~propyl~benzoate
2-~-Toluenesulfonylethyl-4-(4-oxobutyl)benz-
oate (0.76 mole) is added dropwise during 20 minutes to
a stirred solution 1-(2-aminoethyl)cyclohexanol (129.5
g., 0.91 m~le) in toluene (500 ml.). The mixture is
stirred at 30C. for 30 minutes and then refluxed using
a Dean-Stark water separator for 30 minutes until the
formed water is removed. Toluene (500 ml.), methyl thio-
glycollate (118.7 g., 0.12 mole) and triethylamine (30
ml.) are then added. The solution is boiled under reflux
for 21 hours. It is then cooled, washed with 2N hydro-
chloric acid and water, and dried over sodium sulfate.
Evaporation of the solvent gives the title product as a
viscous oil.
Step D: Preparation of Compound IA by Reductive Elimi-
nation
The product (2 mmol.) obtained in Step C
directly above is dissolved in 35 ml. of benzene and
~L~.2~5
-82- 16068Y
1 treated at room temperature with 1,5-diazabicyclo[4.3.0]-
non-5-ene (2 mmol.) under nitrogen. After gas evolution
has subsided, the reaction mixture is concentrated under
reduced pressure to an oily residue which is dissolved
in 50 ml. of chloroform. This solution is then washed
with lN HCl solution ~3 x 50 ml.) a~d brine, then dried
over anhydrous magnesium sulfate and conc~ntrated to give
the title compound as an oil which crystallizes.
EXAMPLE 54
Preparation of Compound I from Benzyl 4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl~-~-oxo-2-thiazolidinyl]propyl7-
benzoate by Nonhydrolytic Ester Cleavage
A mixture of benzyl 4-~3-[3-[2-(1-Hydroxycyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate (10
mmol., obtained in Example 40, Step A), potassium thio-
cyanate (20 mmol., 2 equiv. per carboxylate) in dimethyl-
formamide (DMF, 5 ml.) is heated under reflux for 3 hours.
Water is added to the cooled reaction mixture and the
resulting solution is washed with ether to remove non-
acidic organic materials. The aqueous phase is acidifiedwith 2N HCl solution and extracted with chloroform. The
combined chloroform extracts are washed with water and
brine, then dried over anhydrous magnesium sulfate and
concentrated to give the title compound as an oil which
crystallizes on standing.
EXAMPLE 55
Preparation of I by Electrolysis of 2,2,2-Trichloroethyl
4-~3-[3-[2-(1-hy~roxycyclohexyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl~benzoate
A cylindrical vessel ~lS0 ml.) is fitted with
two side arms which are separated from the main compart-
ment with coarse glass frits. A mercury pool electrode
2~5
-83- 16068Y
1 is placed into the main compartment and a saturated calo-
mel reference electrode is placed in one side arm and a
platinum sheet in the other side arm. The cylinder is
capped with a large ground-glass joint bearing a gas
inlet tube and an exit stopcock. The lower portion of
the apparatus is encased in a water jacket. ~ithium per-
chlorate (0.1 M) in methanol is added to the cell and
the side arms. To the solution in the main compartment
(Ca. 20 ml~) is added 2,2,2-trichloroethyl 4 ~3-[3-[2-
(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]prop-
yl~benzoate (1.97 mmol., obtained in Example 50, Step C)
and the mixture is degassed with an argon stream for 30
minutes. Then the potentiostat is engaged to provide a
potential difference of -1.65V between the mercury pool
and the reference electrode. The current drops off slow-
ly over 2 hours and reaches a steady value of about 3mA.
The reaction mixture is separated from the mercury, con-
centrated at reduced pressure and acidified with lN HC1
solution. The aqueous solution is extracted with chloro-
form (3 x 40 ml.). The combined chloroform extracts aredried over magnesium sulfate and concentrated to give the
title compound.
EXAMPLE 56
Preparation of Compound I by Nonhydrolytic Ester Cleavage
of 9-Methyleneanthracene ~-~3-[3-[2-(1-hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate
Step A: Preparation of 9-Methyleneanthracene-9-~3-[2-
(1,3-dioxolanyl)]propyl~benzoate
4-~3-[2-(1,3-Dioxolanyl)]propyl}benzoic acid
(5 mmol.) and 9-chloromethylanthracene (S mmol.) is added
to a solution of acetonitrile (100 ml.) containing tri-
ethylamine (S mmol.). The resulting solution is refluxed
z~5
-84- 16068Y
1 for 6 hours,cooled and poured into 200 ml. of water. The
aqueous solution is then extracted with chloroform (3 x
50 ml.). The combined organic extracts are washed in
succession with 2N HCl solution (2 x 20 ml.), 10% sodium
bicarbonate solution t2 x 20 ml.), and brine. The ex-
tracts are dried over anhydrous potassium carbonate and
evaporated to give the title compound.
Step B: Preparation of 9-Methyleneanthracene 4-(4-oxo-
butyl)benzoate
This compound is prepared by the same procedure
as described in Example 1, Step A-2, except that 9-meth-
yleneanthracene 4-~3-[2-(1,3-dioxolanyl)]propyl~benzoate
is substituted for ethyl 4-~3-[2-(1,3-dioxolanyl)]propyl}-
benzoate. In this way, the title compound is obtained
as an oil.
Step C: Preparation of 9-Methyleneanthracene 4-~3-[3-
[2-(l-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoli
dinyl]propyl~benzoate
The synthesis of this compound is carried out
by the procedure of Example 47, Step B, except that t-
butyl-4-(4-oxobutyl)benzoate is replaced by an equivalent
quantity of 9-methyleneanthracene-4-(4-oxobutyl)benzoate.
The title compound is then isolated as a viscous oil.
Step D: Preparation of Compound I from 9-Methylene-
anthracene-4-~3-[3-~2-(1-~ydroxycyclohexyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl~benzoate
9-Methyleneanthracene 4-~3-[3-[2-(1-Hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate
(2 mmol~) is dissolved in 20 ml. of dry dimethylformamide
and cooled to -20C. under an atmosphere of nitrogen.
Sodium methyl mercaptide (3 mmole) is added to the reac-
tion mixture with stirring. After 1 hol~r, the reaction
Z~5
-85- 16068Y
1 mixture is poured into 150 ml. of water and washed with
ether. The aqueous layer is then acidified with lN HCl
solution and extracted with chloroform. The combined
chloroform extracts are washed with brine, dried over
anhydrous magnesium sulfate, and concentrated to give
the title compound as a solid.
EXAMPLE 57
Preparation of Compound IA
Step A: Preparation of Methyl 4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~-
benzoate
This procedure is carried out in the same
manner as Example 40, Step A, except that methanol is
substituted in equivalent amounts for benzyl alcohol.
In this way, the title compound is obtained as an oil.
Step B: Preparation of Compound I by Non-Hydrolytic
Cleavage of Methyl 4-~3-[~-[2-(1-hydroxycyclo-
hexyl)ethyl~-4-oxo-2-thiazolidinyl]propyl}benzo-
ate
Methyl 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl~benzoate (2.10 mmol.) is
added to a suspension of anhydrous lithium iodide (6.5
mmol.) in 40 ml. of freshly distilled 2,6-lutidine under
argon. The resulting suspension is brought to reflux,
whereby the reaction mixture becomes homogenous. After
8 hours, the solution is cooled to room temperature and
partitioned between methylene chloride/2N HCl solution
(2:1 by volume). The aqueous phase is extracted with
methylene chloride (2 x 30 ml.) and the combined organic
extracts back washed with 2N HCl solution and brine.
The extracts are dried lsodium sulfate) and evaporated
~.2'~Z~5
-86- 16068Y
1 under reduced pressure to give an oily residue which
affords the title compound in analytical form after tri-
turation with acetonitrile.
EXAMPLE 58
A: Preparation of Compound I by Hydrogenolysis of 4-~3-
[3-[2-(1-Hydroxycyclohexy~)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl~-3-chlorobenzoic Acid
A solution of 4-~3-[3-[2-(1-hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl}-2-chlorobenzoic acid
(prepared in Example 9) (298 mg., 0.7 mmol.) in dimethyl-
formamide (3 ml.) containing 200 mg. of a 20% palladium
hydroxide on charcoal catalyst is shaken with hydrogen at
25C. and atmospheric pressure for 22 hours. When the
theoretical amount of hydrogen is absorbed, the catalyst
is removed by filtration. The filtrate is diluted with
20 ml. of water. The oily product is taken up in chloro-
form, washed with water, and dried over magnesium sulfate.
The solvent is evaporated to leave compound IA as a cry-
stalline solid.
B: Preparation of Compound I
A--
By following the same procedure as in A above
but substituting an equivalent quantity of 4-~3-[3-[2-
(l-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]prop-
yl~-3-chlorobenzoic acid (prepared in Example 8) for the
substituted 3-chlorobenzoic acid used in A above, there
is obtained compound IA as a crystalline solid.
l~.Z4Z9~5
-87- 16068Y
1 EXAMPLE 59
Preparation of Compound I by Hydrogenation of 4-~3-[3-
[2-(1-Hydroxycyclohexyl)e~hyl)-4-oxo-2-thiazolidinyl]-1-
~ro~vnYl~benzoic Acid
~,
S Step A: Preparation of Ethyl 4-(3-Formyl-l-propynyl)-
benzoate
Step A-l: Preparation of Ethyl 4-[4-(Tetrahydro-2~I-
pyran-2-yloxy)-1-butynyl]benzoate
A solution of n-butyl lithium (2.25 M in hexane,
4.44 ml., 0.1 mole) is added to a solution of diisoprop-
ylamine (10.1 g., 0.1 mole) in tetrahydrofuran (95 ml.)
at -5C. The solution is stirred at -5C. for 0.5 hours
and then treated with a solution of _-ethynylbenzoic acid
(7.3 g., 0.05 mole) in tetrahydrofuran (10 ml.). This
solution is stirred at 0C. for 1 hour and then 2-(tetra-
hydro-2H-pyran-2-yloxy)ethylbromide (10.4 g., 0.05 mole)
is added. The resulting solution is allowed to stand
without further cooling for 18 hours. It is then poured
onto ice. The mixture is acidified with 2N hydrochloric
acid and extracted with methylene chloride. The extracts
are dried over magnesium sulfate and evaporated to give
a semi-solid residue. A mixture of this material, ethyl
iodide (12.2 g., 0.078 mole), potassium carbonate (8.9
g., 0.065 mole) and dimethylformamide (40 ml.) is stirred
at 25C. for 2 days. The mixture is poured into water.
The product is taken up in ether and dried over magnesium
sulfate. Evaporation of the solvent leaves the title
compound as a yellowish oil.
Step A-2: Preparation of Ethyl 4-(4-Hydroxy-l-butynyl)-
benzoate
A solution of ethyl 4-[4-(tetrahydro-2H-pyran-
2-yloxy)-1-butynyl]benzoate (10.8 g., 0.036 mole) and
-88~ Z ~ S
1 pyridinium ~-toluenesulfonate (1.0 g., 0.004 mole) in
ethanol (25 ml.) is heated at 75C. for 10 hours. The
solution is diluted with ether, washed with water and
dried over magnesium sulfate. Evaporation of the sol-
vent at reduced pressure affords the title hydroxyester
as an oil.
Step A-3: Preparation of Ethyl 4-(3-Formyl-l-propynyl)-
benzoate
A solution of the ester product of Step A-2
(6.1 g., 0.028 mole) in methylene chloride (5 ml.) is
added with stirring to a solution of chromium trioxide
tl6.8 g., 0.168 mole) in pyridine (26.58 g., 0.336 mole)
and methylene chloride (100 ml.). The resulting mixture
is stirred for 2 hours at 25-30C. The methylene chlor-
ide solution is decanted from solids, washed with dilute
hydrochloric acid and water, and dried over magnesium
sulfate. The solution is then evaporated. The residue
is triturated with ether. The ether extract is filtered,
washed with sodium ~icarbonate solution and water, dried
(magnesium sulfate) and concentrated to yield the title
aldehyde as an oil.
Step B: Preparation of Ethyl 4-~3-[3-[2-(1-Hydroxycyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]-1-propynyl~-
benzoate
Ethyl 4-(3-formyl-1-propynyl)benzoate (16.4 g.,
0.76 mole) is added dropwise during 20 minutes to a
stirred solution of l-(2-aminoethyl)cyclohexanol prepared
by treatment of hydroxycyclohexyl acetonitrile with lith-
ium tetrahydridoaluminate (129.5 g., 0.91 mole) in tolu-
ene (500 ml.). The mixture is stirred at 30C. for 30
minutes and then refluxed in a Dean-Stark water separator
for 30 minutes until the formed water is removed. Tolu-
ene (500 ml.), methyl thioglycollate (118.7 g., 1.12
-89- 16068Y
1 mole) and triethylamine (30 ml.) are then added. The
solution is boiled under reflux for 21 hours. It is then
cooled, washed with 2N hydrochloric acid and water, and
dried over sodium sulfate. Evaporation of the solvent
gives the title product as a viscous oil.
Step C: Preparation of 4-~3-[3-~2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]-1-propynyl~benzoic
Acid
A solution of the crude product obtained in
Step B above (338 g.) in methanol (3500 ml.), water (750
ml.) and 5N sodium hydroxide solution (400 ml.) is stirred
at room temperature for 16 hours. The solution is con-
centrated at reduced pressure to a volume of 2500 ml. and
diluted with water (4000 ml.). The solution is extracted
lS with ether and then acidified with dilute hydrochloric
acid to precipitate the title compound as a viscous oil
that crystallizes.
Step D: Preparation of Compound I by Catalytic Hydrog-
enation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-
4-oxo-2-thiazolidinyl]-1-propynyl~benzoic Acid
4-~3-[3-[2-(1-Hydroxycyclohexyl)e~hyl]-4-oxo-
2-thiazolidinyl]-1-propynyl~benzoic acid (7.7 g., 0.02
mole) in ethanol (125 ml.) is hydrogenated over 2.5 g.
of a 5% Pd on charcoal catalyst at 1 atmosphere pressure
and 27C. When the theoretical amount (0.04 mole) of
hydrogen has been absorbed, the catalyst is filtered off
and the solvent evaporated to yield the title compound
as a viscous oil which crystallizes.
2~5
~90~ 16068Y
1EXAMPLE 60
Preparation of 4-~3-[3-[2-~1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid by Hydrogenation
of an Olefinic Bond
Step A: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]-Z-l-propenyl~benzo-
ic Acid _
4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]-l-propynyl}benzoic acid (7.7 g., 0.02 mole)
10in ethanol (125 ml.) is hydrogenated over 1.5 g. of a
Lindlar catalyst at 1 atmosphere pressure and 27C. When
the theoretical amount (0.02 mole) of hydrogen has been
absorbed, the catalyst is filtered off and the solvent
evaporated to yield the title compound as a viscous oil.
5 Step B: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]-Z-l-propenyl~benzoic acid (7.7 g., 0.02
mole) in ethanol (125 ml.) is hydrogenated over 2.5 g. of
a 5~ Pd on charcoal catalyst at 1 atmosphere pressure and
27C. When the theoretical amount (0.02 mole) of hydro-
gen has been absorbed, the catalyst is filtered off and
the solvent evaporated to yield the title compound as a
viscous oil which crystallizes. (Also illustrated in
Example 12.)
EXAMPLE 61
Preparation of Compound IA
A: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)eth-
yl]-4-oxo-2-thiazolidinyl]propyl~phenyl Bromide
30 4-Bromophenyl butyraldehyde (20 mmoles) is added
dropwise to a stirred solution of l-amino-2-~1-(tetrahydro-
2H-pyran-2-yloxy)cyclohexyl]ethane in carbon tetrachloride
:~.2~Z~
-91- 16068Y
1 (l ml.) maintained at 25C. The resulting mixture is
stirred for 30 minutes before being treated with anhydrous
sodium sulfate (4 g.). Stirring is continued for 2 hours.
The solid is removed by filtration and washed with a small
quantity of benzene. The combined filtrate and washings
are diluted with benzene (70 ml.), treated with mercapto-
acetic acid (1.84 g., 20 mmole.) in one portion, and then
refluxed in a Dean-Stark apparatus for 16 hours. The
reaction mixture is allowed to cool to room temperature,
subsequently washed with dilute hydrochloric acid and 5%
sodium bicarbonate, dried over anhydrous magnesium sul-
fate, and filtered. Evaporation ln vacuo affords an oil
residue which is dissolved in methanol (50 ml.) plus con-
centrated hydrochloric acid (0.2 ml.). The resulting
mixture is stirred at ambient temperature for 3 hours,
diluted with water, and extracted with ether. The ether-
eal extract is washed with dilute sodium bicarbonate,
dried over anhydrous magnesium sulfate, filtered, and
concentrated to give an oil residue. The oil residue is
then applied to a silica gel column (1~0 g.) with chloro-
form. Elution with chloroform-methanol (100:1; v:v; 700
ml.) gives impure material. Further elution with the
same eluant provides the title compound as an oil suitable
for carboxylation.
B: Preparation of Compound IA
A solution of 20 mmoles of 4-~3-[3-[2-(l-hy-
droxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~-
phenyl bromide in 50 ml. of anhydrous ether is slowly
added to a stirred mixture of 40 mmoles of magnesium
turnings in 50 ml. of anhydrous ether to which has been
added one mmole of 1,2-dibromoethane. When the reaction
z~,~
~92- 16068Y
1 ceases, the mixture is poured into a mixture of 200 mmoles
of dry ice in 100 ml. of ether with good agitation. After
the dry ice has evaporatedj the resulting halomagnesium
salt is acidified with dilute hydrochloric acid and the
layers are separated. The ethereal extract is washed
with water, dried over anhydrous magnesium sulfate, and
filtered. Upon cooling the filtrate, the title compound
precipitates as a solid, which is collected by filtration.
The product is recrystallized from chloroform-ether.
EXAMPLE 62
Preparation of Compound I by Carboxylation of 4-~3-[3-
[2-(l-Hydroxycyclohexyl)e~hyl]-4-oxo-2-thiazolidinyl~-
propyl~phenyl bromide Using n-Butyl Lithium and Carbon
Dioxide
Forty mmoles of 2.5 N _-butyl lithium in hexane
is slowly added to a cold solution of 20 mmoles of 4-~3-
[3-[2-(l-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-
propyl~phenyl bromide in 50 ml. of anhydrous tetrahydro-
furan maintained at -40C. under a nitrogen atmosphere.
The lithio derivative so prepared is poured into a mixture
of 200 mmoles of dry ice in lO0 ml. of ether with good
agitation. After the dry ice has evaporated, the result-
ing lithium salt is acidified with dilute hydrochloric
acid and the layers are separated. The ethereal extract
is washed with water, dried over anhydrous magnesium
sulfate, and filtered. Upon cooling the filtrate, the
title compound precipitates as a solid, which is collec-
ted by filtration. The product is recrystallized from
chloroform-ether to give the analytical sample.
3Z~5
~93- 16068Y
1 EXAMPLE 63
Process of Compound IA (Coupling Reaction)
Step A: Preparation of 2-(3-Chloropropyl)-3-[2-(l-
hydroxycyclohexyl)]-4-thiazolidinone
A mixture of 4-chlorobutyraldehyde ~15 mmol.),
2-(1-hydroxycyclohexyl)ethylamine (15 mmol.) and p-tolu-
enesulfonic acid hydrate (a few crystals) in benzene
(150 ml.) is refluxed under azeotropic conditions for
1.5 hours. Subsequently, it is treated with methyl mer-
captoacetate (15 mmol.) and triethylamine (25 mmol.).
The resulting mixture is heated at reflux for 5 hours
and then cooled to room temperature. The reaction mix-
ture is washed with lN HCl and 5~ sodium bicarbonate,
dried over anhydrous magnesium sulfate, and filtered.
Concentration of the filtrate ln vacuo leads to the title
compound.
Step B: Preparation of 3-[2-(1-Hydroxycyclohexyl)]-2-
(3-iodo~ropyl)-4-thiazolidinone
Sodium iodide (35 mmol.) is added to a solution
20 of 2-(3-chloropropyl)-~-[2-(1-hydroxycyclohexyl)]-4-thia-
zolidinone(10 mmol.) in acetone (150 ml.). The resulting
mixture is refluxed for 7 hours and then cooled to room
temperature. The reaction mixture is poured into cold
water and extracted with ether twice. The combined ex-
tracts are washed with 5% sodium bisulfate, brine, dried
over anhydrous magnesium sulfate, and filtered. The
filtrate is evaporated under vacuum to give a residue
which is purified by column chromatography on silica gel
to provide the title compound.
l~.Z9~2~5
_94_ 16068Y
l Step C: Preparation of Compound IA Using an Organocopper
Reagent (II)
A solution of 4-bromobenzoic acid (10 mmol.) in
tetrahydrofuran (THF) (20 ml.) is added to a stirred sus-
pension of lithium hydride (11 mmol.) in THF (120 ml.)at 0C. under a nitrogen atmosphere. The resulting mix-
ture is stirred at 0C. for 1 hour, then cooled to -70C.
and treated with _-butyl lithium (11 mmol.). After
stirring the mixture at -70C. for one hour, cuprous
iodide (21 mmol.) is added and stirring is continued for
another hour. Then, the mixture is treated with a solu-
tion of freshly prepared 3-[2-(l-hydroxycyclohexyl)]-2-
(3-iodopropyl)-4-thiazolidinone (10 mmol.) in THF (10
ml.). After the completion of this addition, the result-
ing mixture is stirred at -70C. for 1 hour, subsequently,
allowed to warm and stirred at -10C. for 3 hours. The
reaction mixture is poured into an ice-cold mixture of
20% ammonium sulfate (40 ml.) and lN HCl solution (40
ml.) and extracted with ether. The organic phase is
separated, washed with 20% ammonium sulfate solution and
brine, dried over anhydrous magnesium sulfate, and fil-
tered. Evaporation of the filtrate ln vacuo leaves a
residue which is purified by column chromatography on
silica gel to provide the title compound.
EXAMPLE 64
Preparation of Compound IA by Alkylation of Thiazolidin-
one Nitrogen _ _
Step A: Preparation of 1-(2-Iodoethyl)cyclohexanol
A solution of l-[2-(p-bromophenylsulfonyloxy)-
ethyl]cyclohexanol (72.8 g., 0.2 mole) and sodium iodide
(90 g., 0.6 mole) in acetone (900 ml.) is allowed to
,
Z~5
~95~ 16068Y
1 stand at 25C. for 21 hours. Most of the acetone is
then removed by distillation at reduced pressure. The
residue is treated with 400 ml. of water. The oily pro-
duct is taken up in ether, washed with water, and dried
over magnesium sulfate. Evaporation of the solvent at
reduced pressure leaves the title iodoalcohol as a yellow
oil weighing 49 g. which slowly crystallizes, m.p. 34-
36.5C.
Step B-l: Preparation of Ethyl 4-[3-(2,5-dihydro-4-eth-
oxy-2-thiazolyl)propyl]benzoate
Triethyloxonium tetrafluoroborate (11 mmol.)
is added in one portion to a stirred solution of ethyl
[3-(4-oxo-2-thiazolidinyl)propyl]benzoate (10 mmol.) in
methylene chloride (100 ml.). The resulting mixture is
stirred at room temperature for 20 hours. It is then
washed with 5% sodium carbonate solution, dried over an-
hydrous magnesium sulfate, and filtered. Concentration
of the filtrate under reduced pressure affords the title
compound.
Step B-2: Preparation of Lithium 4-[3-(2,5-dihydro-4-
ethoxy-2-thiazolyl)~ropyl]benzoate
-
Lithium hydroxide solution (5N, 2.2 ml., 11
mmol.) is added to a solution of ethyl 4-[3-(2,5-dihydro-
4-ethoxy-2-thiazolyl)propyl]benzoate (9 mmol.) in 10%
aqueous methanol (40 ml.). The resulting mixture is
stirred at room temperature for 15 hours. The reaction
mixture is evaporated ln vacuo to dryness to leave the
title compound as a viscous oil.
Step C: Preparation of Compound IA by N-Alkylation of
Lithium 4-[3-(2,5 Dihydro-4-ethoxy-2-thiazolyl)-
propyl]benzoate
~ mixture of freshly prepared lithium
Z~5
-96- 16068Y
1 4-[3-(2/5-dihydro-4-ethoxy-2-thiazolyl)propyl]benzoate
(9 mmol.) and 1-(2-iodoethyl)cyclohexanol (10 mmol.) in
dimethylformamide (50 ml.) is stirred at room temperature
for 15 hours, then heated on a steam bath for 1 hour.
The reaction mixture is allowed to cool to room tempera-
ture, then poured into cold water. It is treated with
lN HCl solution until becoming acidic as indicated by
Congo-Red paper. Ether is then used for extraction. The
ethereal extract is washed twice with brine, dried over
anhydrous magnesium sulfate, and filtered. The filtrate
is concentrated under vacuum to give a viscous residue
which is purified by column chromatography to provide the
title compound.
EXAMPLE 65
Preparation of Compound I by N-alkylation of Ethyl 4-[3-
(4-oxo-2-thiazolidinyl)prApyl]benzoate
Step A: Preparation of 4-[3-(4-Oxo-2-thiazolidinyl)prop-
yl]benzoic Acid
Sodium hydroxide solution (5N, 3 ml., 15 mmol.)
is added to a stirred mixture of ethyl 4-[3-(4-oxo-2-thia-
zolidinyl)propyl]benzoate (8 mmol.) in 10% aqueous meth-
anol (50 ml.). The resulting mixture is stirred at room
temperature for 5 hours, acidified, and extracted with
chloroform. The organic phase is separated, dried and
filtered. Evaporation of the filtrate yields a residue
which is purified by column chromatography to provide the
title compound.
Step B: Preparation of Compound I by N-Alkylation of
4-[3-(4-Oxo-2-thiazolidin~l)propyl]benzoic Acid
A solution of 4-[3-(4-oxo-2-thiazolidinyl)prop-
yl]benzoic acid (10 mmol.) and 1-(2-iodoethyl)cyclohexanol
1~.24Z~S
~97~ 16068Y
l (10 mmol.) in dimethylformamide (15 ml.) is added drop-
wise to a stirred suspension of sodium hydride (22 mmol.)
in DMF (30 ml.) at 0C. under a nitrogen atmosphere.
After completing this addition, the resulting mixture is
allowed to warm to room temperature and is stirred for 2
hours. The reaction mixture is poured into cold water,
acidified (Congo-Red paper) with lN HCl solution and ex-
tracted with ether. The ethereal extract is washed with
brine, dried, and filtered. The filtrate is concentrated
ln vacuo to give a residue which is purified by column
chromatography on silica gel to provide the title compound.
EXAMPLE 66
Preparation of Compound I by Grignard Reaction with N-
Substituent and 1,5-DihaloApentane
5 Step A: Preparation of Benzyl 4-[3-(4-oxo-2-thiazolidin-
yl)propyl]benzoate
A mixture of benzyl 4-(4-oxobutyl)benzoate
(0.113 mole), mercaptoacetamide (0.339 mole), p-toluene-
sulfonic acid monohydrate (2S0 mg.), and benzene (290 ml.)
is refluxed under nitrogen for 2 hours employing a Dean-
Stark constant water separator. The cooled reaction
mixture is poured into water (600 ml.) and the resulting
oil is extracted into ether. The combined extracts are
washed well with water and dried over anhydrous magnesium
sulfate. The solvent is removed under vacuum to give the
title compound as a solid. After triturating with cyclo-
hexane (75 ml.), a solid is obtained which may be recry-
stallized from butyl chloride.
Step s: Preparation of Benzyl 4-~3-[3-(2-Carboethoxy-
ethyl)-4-oxo-2-thiazolidinyl]propyl~benzoate
senzyl 4-[3-(4-oxo-2-thiazolidinyl)propyl]benz-
oate (0.05 mol.) is dissolved in 35 ml. of 1:1 benzene-
:::
Z ~`~ 5
98 16068Y
1 dimethylformamide (D~F), and the solution is added drop-
wise during 30 minutes to a suspension of sodium hydride
(0.055 mol.) in 50 ml. of 1:1 benzene-DMF. The tempera-
ture is held at 30C. during the addition by means of a
cold water bath. The mixture is stirred for an additional
15 minutes and then treated during 15 minutes with ethyl
3-bromopropionate. The mixture is stirred and heated at
55-60C. for 3.5 hours. The mixture is cooled and poured
into 200 ml. of water. The product is taken up in ether,
washed with water, and dried over magnesium sulfate.
Evaporation of solvent at reduced pressure gives the
crude product as a viscous oil.
The crude product is chromatographed on a col-
umn containing 300 g. of silica gel; elution is with
chloroform followed by 2% methanol in chloroform. Frac-
tions are combined on the basis of tlc on SiO2 with 2%
methanol to give the product as a viscous oil
Step C: Removal of the Benzyl Group by Hydrogenolysis
in the Preparation of 4-~3-[3-(2-Carboethoxy-
ethyl)-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
~ enzyl 4-~3-[3-(2-carboethoxyethyl)-4-oxo-2-
thiazolidinyl]propyl~benzoate (0.02 mole) in ethanol (125
ml.) is hydrogenated over 2.5 g. of a 5~ Pd on charcoal
catalyst at 1 atmosphere pressure and 27C. ~hen the
theoretical amount (0.02 mole) of hydrogen has been ab-
sorbed, the catalyst is filtered off, the solvent evapor-
ated, and the residue chromatographed on silica gel with
4% methanol in chloroform as the eluant. The title com-
pound is obtained as a colorless, viscous oil.
Step D: Reaction of the Ethyl Ester with 1,5-Dimetallated
Pentane in the Preparation of Compound IA
To 100 mmoles of the product of Step C above,
dissolved in 200 ml. of ether, is slowly added 150 mmoles.
~ . : ,. ........... .
z~ s
~99- 16068Y
1 of 1,5-bis-bromomagnesium pentane in 500 ml. of ether,
maintaining slow reflux. Ater one hour, dilute hydro-
chloric acid is added and the layers are separated. The
ethereal extract is washed with water, dried over anhy-
drous magnesium sulfate, and filtered. Upon cooling thefiltrate, the title compound precipitates, and is collec-
ted by filtration. Compound IA is recrystallized from
chloroform-ether, m.p. 147-148C.
E~AMPLE 67
Preparation of Compound I by Intra-Molecular Cyclization
Using Organometallic Comp~unds
Step A: Preparation of 4-[3-(4-oxo-2-thiazolidinyl)-
propyl]benzoic Acid
The procedure is identical to that of Example
65, Step A, except that an equivalent quantity of 4-(4-
oxobutyl)benzoic acid is substituted for benzyl 4-(4-oxo-
butyl)benzoate.
Step B: Preparation of 4- 3-[3-(2-Cyanoethyl)-4-oxo-2-
thiazolidinyl]propyl benzoic Acid
To 100 mmoles of the sodium salt of the product
of Step A above, in 50 ml. of dioxane, is added 1 mmole
of sodium hydride and 150 mmoles of acrylonitrile. After
heating for 1 hour at 100C, the mixture is cooled, acidi-
fied with dilute hydrochloric acid and extracted with 200
ml. of ether. The ethereal solution of the title com-
pound is dried over magnesium sulfate and used in the
following step.
Step C: Preparation of 4- 3-[3-(8-Chloro~3-oxooctyl)-4-
oxo-2-thiazolidinyl]propyl benzoic Acid
The ethereal solution of Step B above is reac-
ted with 100 mmoles of 5-chlGropentyl magnesium bromide
~. ~
s
-100- 16068Y
l first at -10C. for l/2 hour and finally at reflux for 1
hour and then treated with dilute hydrochloric acid at
room temperature. The layers are separated and the solu-
tion of product is dried over magnesium sulfate.
Step D: Ring Closure to Compound IA
To the ethereal solution of the product of above
Step C is added 200 mmoles of magnesium at reflux, forming
the metal salt of the cyclized product. The salt is
acidified with dilute HCl and the layers are separated.
The ethereal extract is washed with water, dried over
anhydrous magnesium sulfate, and filtered. Upon cooling
the filtrate, the title compound is produced, m.p. 147-
148C.
EXAMPLE 68
Preparation of Compound IA by Grignard Addition of Cyclo-
hexanone
Step A: Preparation of 4-~3-[3-(2-Bromoethyl)-4-oxo-2-
thiazolidinyl]propyl~benzoic Acid from 4-[3-(4-
Oxo-2-thiazolidinyl)propyl]benzoic Acid
4-[3-(4-Oxo-2-thiazolidinyl)propyl]benzoic acid
is dissolved in tetrahydrofuran (25 ml.) under an atmos-
phere of argon. The mixture is cooled to 0C. and treated
with 2 equivalents of n-butyl lithium. The mixture is
stirred at 0C. for l hour and then treated with 20
equivalents of ethylene oxide. The mixture is warmed to
25C. and stirred until complete disappearance of the
starting material is evident by tlc analysis. The reac-
tion mixture is then quenched by the addition of water
acidified with HCl solution and extracted with ether.
The ethereal extracts are dried over magnesium sulfate
-lOl- 16068Y
1 and coneentrated ln vacuo to give 4-~3-[3-(2-hydroxyethyl)-
4-oxo-2-thiazolidinyl]propyl}benzoic acid. This compound
(4.0 mmol.) is then treated with 2 equivalents of tri-
phenylphosphine dibromide in 25 ml. of methylene chloride
at 25C. for 12 hours. The methylene chloride solution
is washed with water and 5~ sodium bicarbonate solution,
dried over sodium sulfate, and conGentrated ln vacuo to
give 4-~3-[3-(2-bromoethyl)-4-oxo-2-thiazolidinyl]propyl}-
benzoic acid.
Step_B: Preparation of Compound IA_
4-~3-[3-(2-bromoethyl)-4-oxo-2-thiazolidinyl]-
propyl}benzoic acid (5.0 mmol.) is dissolved in anhydrous
tetrahydrofuran (25 ml.) and 5 ml. of hexamethylphosphor-
ous triamide. The solution is treated with l equivalent
of _-butyl lithium at 0C. under an argon atmosphere for
15 minutes. Then 5 equivalents of lithium containing 1%
- sodium is added and the reaction mixture is brought to
reflux temperature for 1 hour. Cyclohexanone (1 equiva-
lent) is then added and the mixture is stirred at reflux
for 4 hours or until the starting material is consumed
as analyzed by tlc. The reaction mixture is then poured
into ice-water, acidified with 5% HCl solution and ex-
tracted with ether. The ethereal extract is dried over
anhydrous magnesium sulfate, and filtered. Upon cooling
the filtrate, the title compound precipitates and is
collected by filtration. The product is recrystallized
from chloroform-ether, m.p. 147-148C.
s
-102- 16068
1 EXAMPLE 69
Preparation of Compound IA
Step A: Preparation of 4-[3-(3-Bromomethyl-4-oxo-2-thia-
zolidinyl)propyl]benzoic Acid (C) _
--~COOH <~ ~COOH
>
O ~ CH2O O OH
PBr3
\ /
<~_N~ ~COOH
O Br
4-[3-(4-Oxo-2-thiazolidinyl)propyl]benzoic acid
(5.0 mmol) is treated with formaldehyde (10 equivalents)
in toluene (25 ml.) at 25C. for 24 hours or until thin
layer chromatographic (tlc) analysis shows no starting
thiazolidinone remains. The reaction mixture is then
quenched by the addition of water and extracted with
ether. The ethereal extracts are dried over sodium sul-
fate and concentrated to give the thiazolidinone ~ .
Thiazolidinone ~ (5.0 mmol.) is dissolved in 50 ml. of
ether and treated with phosphorous tribromide for 10 hours~
The reaction mixture is poured into ice-water and extrac-
ted with ether. The ethereal extracts are dried over
sodium sulfate and concentrated to give the bromothi~-
zolidinone ~ O
~.Z~2~5
-103- 1606~Y
1 Step B: Preparation of Compound IA_
~COOH 1 ) Mg IA
o 2)0~o
Bromothiazolidinone ~ (5.0 mmol.) is dissolved
in anhydrous ether (25 ml.) and treated with 5 equival-
ents of magnesium metal under an argon atmosphere. The
mixture is brought to reflux temperature and methylene-
cyclohexane oxide (2.0 equivalents) is added in 5 ml. of
anhydrous ether. The mixture is heated at reflux for 10
hours and poured into ice-water. The solution is extrac-
ted with ether and the ethereal extract is washed with
water, dried over anhydrous magnesium sulfate, and fil-
tered. Upon cooling the filtrate, the title compound,
which precipitates as a solid, is collected by filtration.
The product is recrystallized from chloroform-ether.
EXAMæLE 70
15 Preparation of Compound IA by Hydration of 4-~3-[3-[2-(1-
Cyclohexenyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic
Acid Using Trifluoroacetic Acid
A solution of 4-~3-[3-[2-(1-cyclohexenyl)eth-
yl]-4-oxo-2-thiazolidinyl]propyl~benzoic acid (3.7 g.,
20 0.01 mole) in trifluoroacetic acid (20 ml.) is allowed
to stand at 25C. for 4 hours. Excess trifluoroacetic
acid is then removed by evaporation at reduced pressure.
The oily residue is dissolved in a solution of sodium
hydroxide (2.0 g., 0.05 mole) in water (40 ml.). The
basic solution is acidified with 2N hydrochloric acid.
2~S
-104- 16068Y
l The title compound precipitates as a solid. Recrystal-
lization from acetonitrile-water yields the purified
title compound, m.p. 147-148C. (Also illustrated in
Example 5B.)
EXAMPLE 71
Preparation of Compound I by Oxymercuration-Demercuration
Hydration of 4-~3-[3-[2-(~-Cyclohexenyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~benzoic Acid
A mixture of 4-~3-[3-[2-(l-cyclohexenyl)ethyl]-
4-oxo-2-thiazolidinyl]propyl}benzoic acid (Example 5,
Step A) (3.7 g., 0.01 mole), sodium bicarbonate (1.0 g.,
0.012 mole) and 20 ml. of water is warmed on the steam
bath until a clear solution is obtained. A solution of
mercuric acetate (3.19 g., 0.01 mole) in 10 ml. of water
is added followed by 20 ml. of tetrahydrofuran. The re-
sulting mixture is stirred at 25-27C. for 24 hours.
Then 10 ml. of 3M sodium hydroxide solution is added,
followed by 10 ml. of a 0.5 M solution of sodium boro-
hydride in 3M sodium hydroxide. Mercury is allowed to
settle. The supernatant is decanted and acidified with
6N hydrochloric acid. The liberated oil is taken up in
chloroform, washed with water, and dried over sodium sul-
fate. Evaporation of solvent leaves a residual oil which
is chromatographed on silica gel with 2% methanol in
chloroform elution to yield the title compound as a cry-
stalline solid.
EXAMPLE 72
Preparation of Compound IA by Acid Hydrolysis of Tetra-
hydropyranyl Ether
Step A: Preparation of Ethyl 4-~3-[3-[2~ Tetrahydro-
2H-pyran-2-yloxycyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~benzoate
s
-105- 16068Y
1 Ethyl 4-(4-oxobutyl)benzoate (Example 1, Step
A) (4.15 g., 18.8 mmol.) is added dropwise to a stirred
solution of l-amino-2-[1-(tetrahydro-2H-pyran-2-yloxy)-
cyclohexyl]ethane in carbon tetrachloride (1 ml.) main-
tained at 25C. The resulting mixture is stirred for 30
minutes before being treated with anhydrous sodium sul-
fate (4 g.). Stirring is continued for 2 hours. The
solid is removed by filtration and washed with a small
quantity of benzene. The combined filtrate and washings
are diluted with benzene (70 ml.), treated with methyl-
thioglycollate (20 mmole.) in one portion, and then re-
fluxed in a Dean-Stark apparatus for 16 hours. The re-
action mixture is allowed to cool to room temperature,
subsequently washed with 5% sodium bicarbonate, dried
over anhydrous magnesium sulfate, and filtered. Evapora-
tion ln vacuo affords an oil residue which is applied to
a silica gel column (12~ g.) with chloroform. Elution
with chloroform-methanol (100:1, v:v, 630 ml.) gives the
desired tetrahydropyranyl ester in 32% yield as a pale
yellow oil.
Step B: Saponification of Ester
Sodium hydroxide solution (SN, 2.5 ml., 12.5
mmol.) is added to a stirred mixture of the product of
Example 2, Step B, (5.91 mmol.), methanol (25 ml.) and
water (5 ml.). The resulting mixture is stirred at am-
bient temperature for 16 hours. Then, it is diluted with
water, acidified with oxalic acid at 0C. and extracted
with ether. The ethereal extract is washed with water,
dried over anhydrous magnesium sulfate, and filtered.
Evaporation of the solvent under reduced pressure gives
the desired 4-~3-[3-~2-(1-tetrahydro-2H-pyran-2-yloxy)-
cyclohexyl]ethyl]-4-oxo-2-thiazolidinyl~propyl benzoic
acid as a yellow oil (95%).
Z~5
-106- 16068Y
1 Step C: Preparation of IA_
~S~ ~COOH
~ N ~ - ~ IA
o THPO V
The product of Step B above (5.0 mmol.) is dis-
solved in a mixture of acetic acid, water, tetrahydrofuran
(1:1:1, v:vov, 25 ml.) and the solution was heated at
60C. for 8 hours. Then it is diluted with water and
extracted with ether. The ethereal extract is washed
with water, dried over anhydrous magnesium sulfate, and
filtered. Upon cooling the filtrate, the title compound,
which precipitates as a solid, is collected by filtration.
The product is recrystallized from chloroform-ether.
EXAMPLE 73
Preparation of Compound I by the Simultaneous Hydrolysis
of an Ethvl Ester Tetrahv~ropyranvl Ether
~ ._
The tetrahydropyranyl ester product of Step A,
Example 72, (5.0 mmol.) is dissolved in a mixture of
tetrahydrofuran - 10% hydrochloric acid (1:1, v:v, 25 ml.)
and heated with stirring at 60C. for 8-12 hours. The
reaction mixture is cooled to 25C. and extracted with
ether. The ethereal extract is dried over anhydrous mag-
nesium sulfate, and filtered. Upon cooling the filtrate,the title compound precipitates as a white solid, which
is collected by filtration. The product is recrystallized
from chloroform-ether, m.p. 147-148C.
2~.5
-107- 16068Y
1 EXAMPLE_74
Preparation of Compound IA_
Step A: Preparation of 2-[1-(3-Bromotetrahydro-2H-pyran-
2-yl)oxycyclohexyl]acetonitrile
To a solution of 5.0 mmol. of 2-(1-hydroxycyclo-
hexyl)acetonitrile in 10 ml. of anhydrous pyridine at QC.
is added 5.5 mmol~ of 2,3-dibromotetrahydropyran. The
solution is stirred between 0C. and 25C. until the
starting hydroxy-nitrile disappears, as monitored by
thin layer chromatography. The reaction mixture is
diluted with water and extracted with ether. The ether
extracts are washed with lN cupric sulfate solution to
remove the pyridine and then dried over sodium sulfate.
Removal of solvent by rotary evaporation gives the
desired product.
Step B: Preparation of 1-Amino-2-[1-(3-bromotetrahydro-
2H-pyran-2-yloxy)cyclohexyl]ethane
The nitrile (5.0 mmol.) of Step A above is
selectively reduced with 1.0 equivalent of lithium alu-
minum hydride in ether at -78 to 0C. under an inert
atmosphere of either nitrogen or argon. The isolation
of the product is carried out in the same manner as
described for the corresponding pyranyloxy compound of
Example 2, Step A-3.
25 Step C: Preparation of 4-~3-[3-[2-(1-(3-Bromotetrahydro-
2H-pyran-2-yloxy)cyclohexyl)ethyl]-4-oxo-2-thia-
zolidinyl]propyl~benzoic Acid
The procedures of Example 72, Steps A and B are
repeated, employing the product of Step B above as the
starting material, with resultant production of the title
compound.
~ ~ ,
z~s
-108- 16068Y
1 Step D: Preparation of Compound IA
S ~ COOH
N ~ ~ > IA
The bromotetrahydropyran compound of Step C
above (5.0 mmol.) is dissolved in 10 ml. of 50% aqueous
acetic acid and treated with 1 equivalent of powdered
zinc. The mixture is then heated at reflux until com-
plete disappearance of starting material is apparent by
thin layer chromatography. The mixture is cooled to 25C.
and extracted with ether. The ethereal extracts are
dried over magnesium sulfate and cooled to 0C. Upon
cooling, the desired hydroxy acid precipitates.
EXAMPLE 75
Preparation of Compound IA by Alkylative Hydrolysis of
4-~3-[3-[2-(1-Methylthiomethyloxycyclohexyl)ethyl]-4-oxo-
thiazolidinyl]propyl~benzoic Acid
5 Step A: Preparation of 2-[1-Methylthiomethyloxycyclohex-
yl)acetonitrile
2-(1-Hydroxycyclohexyl)acetonitrile (5 mmol.)
is combined with acetic anhydride (30 ml.) and dimethyl
sulfoxide (30 ml.) and stirred at 23C. for 30 hours.
The reaction mixture is concentrated ln vacuo using a dry
ice-acetone trap and the resulting residual oil is dis-
solved in benzene. The benzene solution is washed with
saturated sodium bicarbonate solution and brine, then
dried over magnesium sulfate and concentrated to give the
title compound as an oil.
z~s
-lO9- 16068Y
Step B: Preparation of 4-~3- [3- [2-(1-Methylthiomethyl-
oxycyclohexyl)ethyl]-4-oxo-thiazolidinyl]propyl}-
benzoic Acid
The procedures of Example 72, Steps A and s,
are repeated using an equivalent amount of the product
obtained in Step A directly above with the resultant pro-
duction of the title compound as an oil.
Step C: Alkylative Hydrolysis to Form Thiazolidinone IA_
S ~COOH
~\ ~ IA
CIH2 -
S-CH3
The methyl thiomethyl ether of IA (5-0 mmol.)
in 20 ml. of anhydrous ether is treated with l.0 equiva-
lent of methyl iodide. The reaction mixture is then
poured into 25 ml. of water and stirred at 25C. until
the hydrolysis is complete as evidenced by thin layer
chromatography. The reaction mixture is then extracted
with ether. The ether extracts are dried over magnesium
sulfate. The desired hydroxy-acid IA is obtained.
~.~.f~ S
-110- 16068Y
1 EXAMPLE 76
Pre aration of Compound I
P A-
Step A: Preparation of 2-(1-Ethoxycarbonyloxycyclohexyl)-
acetonitrile
2-(1-Hydroxylcyclohexyl)acetonitrile (5.0 mmol.)
is dissolved in 50 ml. of pyridine at 0C. and treated
with 1 equivalent of ethylchloroformate. The mixture is
stirred for 24 hours at 0C. and quenched by the addition
of water. The aqueous mixture is extracted with ether
and the ethereal solutions are combined and washed with
5% hydrochloric acid solution, dried over sodium sulfate,
and concentrated in vacuo to give the title compound.
Step B: Preparation of Ethyl 4-~3-[3-[2-(1-Ethoxycarbon-
yloxycyclohexane)ethyl]-4-oxo-thiazolidinyl]-
propyl~benzoate
The procedure of Example 72, Step A, is repeatedusing as starting material an equivalent amount of 2-(1-
ethoxycarbonyloxycyclohexyl)acetonitrile with the resul-
tant production of the title compound.
Step C: Preparation of Compound I~ by Saponification
The product (5.0 mmol.) of Step s above is
treated with 35 ml. of 10% potassium hydroxide in water
at 60C. The mixture is heated at 60C. until thPre is
no evidence of starting material by tlc. The basic solu-
tion is then acidified with 10% aqueous hydrochloric acid
at 0C. and extracted with ether. The ethereal extracts
are dried over magnesium sulfate and cooled to 0C. Upon
cooling, the desired compound IA is produced. The pro-
duct is recrystallized from chloroform-ether, m.p. 147-
30 148C.
s
-lll- 16068Y
1 EXAMPLE 77
Preparation of Compound I~_
Step A: Preparation of 2-(1-Methoxyoxycyclohexyl)aceto-
nitrile
2-(1-Hydroxycyclohexyl)acetonitrile (50.0 mmol.)
is treated with 1 equivalent of sodium hydride and lO
equivalents of methyl iodide in diethyl ether at 25C.
for 24 hours. The product is isolated by quenching the
reaction mixture with water and extracting the product
with ether. The ethereal extracts are dried over mag-
nesium sulfate and concentrated in vacuo to give the
desired l-methoxy derivative.
Step B: Preparation of 4-~3-[3-[2-(1-Methoxycyclohexyl)-
ethyl]-4-oxo-thiazolidinyl]propyl~benzoic Acld
The procedure of Example 72, Steps A and B, are
repeated using as starting material an equivalent amount
of 2-(l-methoxycyclohexyl)acetonitrile in place of the
2-(l-tetrahydropyranyloxy)acetonitrile with resultant
production of the methyl ether of compound IA.
Step C: Preparation of Compound IA_
~S ~ COOH
N ~ > IA
CH3
The product of Step B above in 25 ml. of
chloroform is treated at 25C. with l equivalent of tri-
methylsilyl iodide. The mixture is then stirred at
2~5
-112- 16068Y
1 25C. until the starting material is completely consumed
as evidenced by thin layer chromatographic analysis. The
reaction mixture is poured into water and extracted with
ether. The ethereal extract is washed with water, dried
over anhydrous magnesium sulfate, and filtered. Upon
cooling the filtrate, the title compound is produced.
EXAMPLE 78
Preparation of Compound I
_ - A--
Step A: Preparation of 2~ Benzyloxycyclohexyl)aceto-
nitrile
2-(1-Hydroxycyclohexyl)acetonitrile (5.0 mmol.)
in 50 ml. of anhydrous tetrahydrofuran is treated with
1.0 equivalent of sodium hydride and 1.0 equivalent of
benzyl bromide. The mixture is heated at reflux tempera-
tures until complete disappearance of starting alcohol is
evident by tlc analysis. The reaction mixture is poured
into ice water and extracted with ether. The ethereal
extracts are dried over magnesium sulfate and concentra-
ted _ vacuo to give an oil residue which is purified by
chromatography to provide the title compound.
Step B: Preparation of 4-~3-[3-[2-(1-Benzyloxycyclohex-
yl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic
Acid
The procedure of Example 72, Steps A and B, are
repeated using as starting material an equivalent amount
of 2-(1-benzyloxycyclohexyl)acetonitrile in place of the
tetrahydropyranyloxy nitrile with resultant production
of the title compound.
-113- 16068Y
1 Step C: Preparation of Compound IA by Hydrogenolysis of
4-~3-[3-[2-(1-Benzyloxycyclohexyl)ethyl]-4-oxo-
2-thiazolidinyl~propyl~benzoic Acid
4-~3-[3-[2-(1-Benzyloxycyclohexyl)ethyl]-4-oxo-
2-thiazolidinyl]propyl}benzoic acid (5.0 mmol.) is dis-
solved in ethanol (25 ml.) and treated with 0.05 equiva-
lents of palladium on carbon catalyst. The reaction mix-
ture is then placed under hydrogen at atmospheric pressure
and stirred at 25C. for 24 hours. The solution is fil-
tered and the ethanol removed ln vacuo to give IA. The
product is recrystallized from chloroform-ether, m.p.
147-148C.
EXAMPLE 79
Preparation of Compound I
A--
5 Step A: Preparation of 2-[1-(t-Butyldimethylsilyloxy)-
cyclohexyl]acetonitrile
A mixture of 2-(l-hydroxycyclohexyl)aceto-
nitrile (5.0 mmol.) and t-butyldimethylsilyl chloride
(lO.0 mmol.) in 25 ml. of anhydrous dimethylformamide at
0C. is treated with imidazole (5.0 mmol.). The mixture
is stirred at 25-40C. until starting material is no
longer apparent by tlc analysis. The solution is diluted
with lO0 ml. of ether and washed with brine. The ethereal
extract is dried over sodium sulfate, and concentrated
_ vacuo to give the title product.
Step B: Preparation of 4-~3-[3-[2-(l-(_-Butyldimethyl-
silyloxy)cyclohexyl)ethyl]-4-oxo-2-thiazolidin-
yl]propyl~benzoic Acid
The procedure of Example 72, Steps A and B, are
repeated using as starting material an equivalent amount
of 2-[l-(t-butyldimethylsilyloxycyclohexyl)]acetonitrile
in place of the tetrahydropyranyloxy nitrile with resul-
tant production of the title compound.
2~ ~
-114- 16068Y
1 Step C: Preparation of Compound I
A--
~S ~ COOH
N ~ O-Si ~ (CH3~2 3 IA
O ~ t-Bu
4-~3-[3-[2-(1-t-Butyldimethylsilyloxy)cyclo-
hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid
(5.0 mmol.) is dissolved in 25 ml. of anhydrous tetra-
hydrofuran and treated with 3 equivalents of anhydroustetrabutylammonium fluoride at 25C. for 2 hours. The
reaction mixture is poured into water and extracted
with ether. The ethereal extract is washed with water,
dried over anhydrous magnesium sulfate, and filtered.
Upon cooling the filtrate, the title compound is re-
covered. The product is recrystallized ~rom chloroform-
ether, m.p. 147-148C.
EXAMPLE 80
Preparation of Compound I
A--
Step A: Preparation of t-Butyl 4-~3-[3-[2-(1-(o-Nitro-
benzyloxy)cyclohexyl)ethyl]-4-oxo-2-thIazolidin-
yl]propyl~benzoate
A solution of t-butyl 4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate
(5 mmol.) in pyridine (100 ml.) is treated with o-nitro-
benzyl bromide (6 mmol.) at 25C. The resulting mixture
is stirred until the starting benzoate has completely
disappeared by tlc analysis. The reaction mixture is
then diluted with ether and washed with diluted hydro-
chloric acid, 5% sodium bicarbonate solution, and dried
-115- 1606~Y
1 over sodium sulfate. Removal of the solvent ln vacuo
affords an oil residue which is purified by chromatog-
raphy to provide the title compound.
Step B: Preparation of 4-~3-[3-[2-(1-(o-Nitrobenzyloxy)-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-
benzoic Acid
The product of Step A above is cleaved in a
manner as described in Example 47, Step C, to yield the
title compound.
0 Step C: Preparation of Compound I by Irradiation of
4-~3-[3-[2-(1-(o-NitrobenzAyloxy)cyelohexyl)eth-
yl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A solution of the produet (5.0 mmol.) of Step B
above in methylene chloride is irradiated with li~ht
15 (270 ~300 nm.) at 25C. for 24 hours or until starting
material is no longer evident by thin layer chromatogra-
phy. The reaction mixture is then evaporated to dryness
and the methylene ehloride is replaeed with ether. The
ethereal solution is eooled to 0C., at whieh time the
title compound is recovered by filtration. The produet
is recrystallized from chloroform-ether, m.p. 147-148C.
EXAMPLE 81
Preparation of Compound I
-A--
Step A: Preparation of t-Butyl 4-~3-[3-[2-(1-(2,2,2-Tri-
chloroethoxycarbonyloxy)cyclohexyl)ethyl]-4-oxo-
2-thiazolidinyl]propyl~benzoate
A solution of _-butyl 4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate
(5 mmol.) in pyridine (25 ml.) is treated with 2,2,2-tri-
chloroethylchloroformate (5.5 mmol.) at 25C. and stirred
-116- 16068Y
1 until the starting benzoate is no longer apparent by tlc
analysis. The mixture is poured into ice water and ex-
tracted with ether. The ethereal extract is washed with
saturated cupric sulfate solution, dried over sodium sul-
fate, and concentrated in vacuo to give the title compound.
Step B: Preparation of 4-~3-~3-[2-(1-(2,2,2-Trichloro-
ethoxycarbonyloxy)cyclohexyl)ethyl]-4-oxo-2-
thiazolidinyl]propyl~benzoic Acid
The product of Step A above is cleaved in a
manner as described in Example 47, Step C, to yield the
title compound.
Step C: Preparation of Compound I by Electrolysis of
4-~3-[3-[2-(1-(2,2,2-TrichAloroethoxycarbonyloxy)-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl~-
benzoic Acid
The product (5.0 mmol.) of Step B above is dis-
solved in 25 ml. of tetrahydrofuran-water (1:9, v:v)
and placed in an electrolysis cell with platinum elec-
trodes. The electrolysis is then conducted at 1.5 V and
25C. for 6 hours or until the starting thiazolidinone is
completely consumed as analyzed by thin layer chromatog-
raphy. The reaction mixture is extracted with ether.
The ethereal extract is washed with water, dried over
anhydrous magnesium sulfate, and filtered. The title
compound is recovered as a white solid. The product is
recrystallized from chloroform-ether, m.p. 147-148C.
EXAMPLE 82
Preparation of Compound I
A--
Step A: Preparation of t-Butyl 4-~3-[3-[2-(1-(2-methyl-
~,5-benzo-1,3-dioxolan-2-yl)carbonyloxycyclohex-
yl)ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoate
A solution of t-butyl 4-~3-[3-[2-(1-hydroxycyclo-
2~*S
-117- 16068Y
1 hexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate (5.0
mmol.) and 2-methyl-4,5-benzo-1,3-dioxolan-2-carboxylic
acid (5.0 mmol.) in 25 ml. of tetrahydrofuran is treated
with dicyclohexylcarbodiimide (5.0 mmol.). The mixture
is heated at reflux or 24 hours and then quenched by
pouring into ice water. The aqueous solution is then
extracted with ether. The ethereal extracts are dried
over magnesium sulfate and concentrated ln vacuo to give
the title compound.
Step B: Preparation of 4-~3-[3-[2~ (2-~ethyl-4,5-benzo-
1,3-dioxolan-2-yl)carbonyloxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid
The product of preceeding Step A is cleaved in
a manner as described in Example 47, Step C, to yield the
title compound.
Step C: Preparation of Compound IA_
~S ~C02H
~ N ~ CH3 enzyme > IA
~0
0
A solution of the product (5.0 mmol.) of pro-
ceeding Step 3 in 100 ml. of 0.1 M potassium phosphate
buffer (p~I 6.0-9.0) is treated with chvmotrypsin and
incubated at 25-37C. for 24 hours. The solution is then
extracted with ether and the ethereal extract is washed
with water, dried over anhydrous magnesium sulfate, and
filtered. Upon cooling the filtrate, the title compound
~118- 16068Y
1 precipitates as a solid, which is collected by filtration.
The product is recrystallized from chloroform-ether, m.p.
147-148C.
EXAMPLE 83
Preparation of Compound I
A--
Step A: Preparation of t-Butyl 4-~3-[3-[2-(1-(3-Benzyl-
propionyloxy)cyclohexyl)ethyl]-4-oxo-2-thiazoli-
dinyl]propyl~benzoate
A solution of t-butyl 4-~3-[3-[2-(1-hydroxy-
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate
(5.0 mmol.) and 3-benzoylpropionic acid (5.0 mmol.) in
25 ml. of tetrahydrofuran is treated with dicyclohexyl-
carbodiimide (5.0 mmol.). The mixture is heated at re-
flux for 24 hours and then quenched by pouring into ice
water. The aqueous solution is then extracted with ether.
The ethereal extract is dried over magnesium sulfate and
concentration in _cuo to give the title compound.
5tep B: Preparation of 4-~3-[3-[2-(1-(3-Benzoylpropionyl-
oxy)cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]prop-
yl~benzoic Acid
The product of preceeding Step A is cleaved in
a manner as described in Example 47, Step C, to yield the
title compound.
Step C: P,reparation of Compound I by Aminolysis of 4-
~3-[3-[2-(1-(3-BenzoylpropAionyloxy)cyclohexyl)-
ethyl]-4-oxo-2-thiazoli~inyl]propyl~benzoic Acid
The product (5.0 mmol.) of preceeding Step B is
dissolved in 25 ml. of tetrahydrofuran and treated at
25C. with 2.0 equivalents of hydrazine. The mixture is
heated at reflux until starting material is consumed, as
-
:
2~
-119- 1606~Y
1 analyzed by tlc. Then, it is diluted with water, acidi-
fied with dilute hydrochloric acid, and extracted with
ether. The ethereal extract is washed with water, dried
over anhydrous magnesium sulfate, and filtered. Upon
cooling the filtrate, the title compound precipitates as
a solid, which is collected by filtration. The product
is recrystallized from chloroform-ether, m.p. 147-148C.
EXAMPLE 84
Preparation of Compound I
_ _ A--
Step A: Preparation of 4-(4-Oxobutyl)benzoic Acid
A mixture of ethyl 4-~3-[2-(1,3-dioxolanyl)]-
propyl~benzoate (10 mmol.) in 50~ aqueous acetone (100
ml.) is treated with concentrated sulfuric acid (0.5
mmol.). The resulting mixture is heated at reflux for 24
hours. The reaction mixture is cooled to room temperature
- and diluted with water, followed by ether extraction. The
ethereal extract is washed with brine twice, dried over
anhydrous magnesium sulfate, and filtered. Evaporation of
the filtrate ln vacuo provides the title compound.
0 Step B: Preparation of 4-~4-[N-[2-(1-Hydroxycyclohexyl)-
ethyl]imino]butyl~benzoic Acid
A mixture of 4-(4-oxobutyl)benzoic acid (10
mmol.) and 2-(I-hydroxycyclohexyl)ethylamine (10 mmol.)
in benzene (200 ml.) is refluxed under azeotropic condi-
tions for 7 hours to give a benzene solution of the titlecompound. This solution is used immediately in the sub-
sequent step.
24;5
-120- 16068Y
1 Step C: Preparation of Compound I
A--
HC----~C02H
--~ ) HS-CH2C02H
The freshly prepared benzene solution of 4-~4-
[N-[2-(1-hydroxycyclohexyl)ethyl]imino]butyl~benzoic acid
in Step B is treated with mercaptoacetic acid (10 mmol.).
S The resulting mixture is refluxed under azeotropic condi-
tions for 10 hours. Then, it is allowed to cool to room
temperature and agitated with 0.1 N HCl (100 ml.) and
extracted with chloroform. The organic phase is separated,
washed with brine, dried, and filtered. The filtrate is
concentrated in vacuo to yield a residue which is purified
by column chromatography on silica gel to provide the
title compound.
EXAMPLE 85
Preparation of Compound IA
5 Step A: Preparation of N-[2-(1-Hydroxycyclohexyl)ethyl]-
chloroacetamide
Chloroacetyl chloride (10 mmol.) is dropwise
added to a stirred solution of 2-(1-hydroxycyclohexyl)-
ethylamine (12 mmol.) and triethylamine (20 mmol.) in
benzene (40 ml.) at 10C. After the completion of the
addition, the resulting mixture is allowed to warm up to
room temperature and stirred for 5 hours. Then, the re-
action mixture is diluted with ether and washed with
water. The organic phase is separated, successively
;: ....
-121- 1606~Y
1 washed with lN HCl, 5~ sodium bicarbonate, and brine.
After drying over anhydrous magnesium sulfate, it is fil-
tered and concentrated to afford the title compound as a
viscous oil.
Step B: Preparation of N-[2-(1-Hydroxycyclohexyl)ethyl]-
acetylmercaptoacetamide
Thiolacetic acid (11 mmol.) is dropwise added
to a solution of sodium methoxide (11 mmol.) in methanol
(50 ml.) at 0 ~5C. After completing the addition, the
resulting solution is stirred under a nitrogen atmosphere
at room temperature for 0.5 hours and then treated with a
solution of N-[2-(1-hydroxycyclohexyl)ethyl]chloroacet-
amide (10 mmol.) in methanol (20 ml.). The resulting
mixture is stirred at room temperature for 0.5 hour and
then refluxed for 0.5 hour. It is poured into cold
water, extracted with ether. The ethereal extract is
washed with brine water, dried, and filtered. The fil-
trate is evaporated ln vacuo to yield the title compound.
Step C: Preparation of N-[2-(1-Hydroxycyclohexyl)ethyl]-
mercaptoacetamide
A stirred mixture of N-[2-(1-hydroxycyclohexyl)-
ethyl]acetylmercaptoacetamide (10 mmol.) in methanol (70
ml.) is treated with sodium methoxide (10 mmol.), then
heated at reflux under a nitrogen atmosphere for 2 hours.
The reaction mixture is allowed to cool to room tempera-
ture, poured into cold water, acidified with lN HCl, and
extracted with ether. The ethereal extract is washed with
brine water, dried, and filtered. The filtrate is con-
centrated in vacuo to provide the title compound as a
viscous oil.
2~S
-122- 16068Y
1 Step D: Preparation of Compound IA_
SH
~7 NH ~>o HC -- C02H
OH, Q
A mixture of N-[2~ Hydroxycyclohexyl)ethyl]-
mercaptoacetamide (10 mmol.), 4-(4-oxobutyl)benzoic acid
(10 mmol.) and p-toluenesulfonic acid (a few crystals) in
benzene (lO0 ml.) is refluxed under azeotropic conditions
for 10 hours. The reaction mixture is concentrated ln
vacuo to leave a residue which is chromatographed on a
silica gel column to give purified title compound.
EXAMPLE 86
Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid
Step ~: Preparation of Ethyl 4-~3-[3-[2-(1-Hydroxycyclo-
cyclohexyl)ethyl]-1,4-dioxo-2-thiazolidinyl]-
propyl}benzoate
Sodium metaperiodate (0.75 g., 3.5 mmoles) is
added to a cold (0-5C.) solution of ethyl 4-~3-[3-[2-(1-
hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-
benzoate (1.42 g., 3.4 mmoles) in methanol (30 ml.) and
water (5 ml.). The resulting mixture is stirred without
further cooling for 16 hours. The precipitated solid is
removed by filtration. The filtrate is diluted with water
and extracted with ether. The extract is washed with
water, dried over sodium sulfate, and evaporated to leave
the title product as a viscous oil.
~ ~ z~2r,~,5
-123- 16068Y
Preparation of 4-~3-[3-~2-(1-Hydroxycyclohexyl)-
ethyl]-1,4-dioxo-2-thiazolidinyl]propyl~benzoic
Acid
A solution of the product of Step A above (1.48
g., 3.4 mmoles) and sodium hydroxide (0.4 g., 10 mmoles)
in methanol (20 ml.) and water (4 ml.) is allowed to stand
at 27C. for 24 hours. The solution is diluted with water
and acidified with 6N hydrochloric acid. The liberated
acid is taken up in chloroform, washed with water, and
dried over sodium sulfate. Evaporation of the solvent
provides the title compound as a very viscous yellow oil.
Step C: Preparation of 4-~3-[3-[2-(1-~ydroxycyclohexyl)-
ethyl]-4-oxo-2-thiazolidinyl]propyl~benzoic Acid
A solution of the sulfoxide product of Step B
15 above (4.07 g., 10 mmoles) in ethanol (50 ml.) is placed
in a steel pressure vessel along with 1.5 g. of a 5~ pal-
ladium on charcoal catalyst. The vessel is sealed and
charged with hydrogen to a pressure of 65 atmospheres.
The vessel is then rocked and heated at 85C. for a per-
iod of 3 days until the theoretical amount of hydrogen
has been absorbed. The vessel is cooled and opened. The
catalyst is removed by filtration and the ethanol evapor-
ated to leave the title compound as an oil which crystal-
lizes.
2~5
-1~4- 16068Y
1EXAMPLE 87
Preparation of Compound IA_
H-C ~ COOH Na2S
N~ ~ ~ ~ (Step A)
HO J CH 2 - CH Cl 2
S ~ COOH +
N ~ H > IA (Step B)
Cl ~
Step A: Preparation of 4-~3-[3-[2-(1-Hydroxycyclohexyl)-
ethyl]-4-chloro-2,3-dihydro-2-thiazolyl]propyl}-
benzoic Acid
A solution of (5.0 mmol.) 4-~4-[N-[2-(1-hydroxy-
cyclohexyl)ethyl]imino]butyl~benzoic acid in tetrahydro-
furan/water is treated with 1.0 equivalent of l-bromo-
2,2-dichloroethane and 1.0 equivalent of sodium sulfide
at 40C. for 8 hours. The aqueous solution is then ex-
trac"ed with ether, dried over sodium sulfate, and con-
centrated ln vacuo to yield the title compound.
- Step B: Preparation of Compound I by Hydrolysis of 4-
~3-[3-[2-(l-HydroxycycloheAxyl)ethyl]-4-chloro-
2,3-dihydro-2-thiazolyl]propyl~benzoic Acid
The product of Step A above (5.0 mmol.) is
treated with 25 ml. of 5% hydrochloric acid solution for
4 hours at 25C., until complete conversion to compound
IA is evident from tlc analysis. The mixture is extrac-
ted with ether. The ethereal extract is washed with
~.Z~ 5
-125- 16068Y
1 water, dried over anhydrous magnesium sulfate, and fil-
tered. Upon cooling the filtrate, the title compound
precipitates as a solid, which is collected by filtra-
tion.
EXAMPLE 88
Preparation of 4-~3-[3-[2-(1-HydroxycycIohexyl)ethyl]-4-
oxo-2-thiazolidinyl]propyl~benzoic Acid
HC-- ~C02H
< SH + O + -2H2O
C02H NH2~
~0 ~J
<~; ~ C02H
O ~
A mixture of 4-(4-oxobutyl)benzoic acid (10
mmol.), 2-(1-hydroxycyclohexyl)ethylamine (10 mmol.) and
mercaptoacetic acid (10 mmol.) in benzene (150 ml.) is
refluxed under azeotropic conditions for 12 hours. The
reaction mixture is concentrated to give a viscous oil
residue which is purified by column chromatography on
silica gel to provide the title compound.
